Compositions comprising cytisine in the treatment and/or prevention of addiction in subjects in need thereof

ABSTRACT

Methods of treatment of addiction and/or dependence, methods of promoting cessation of various addictions, such as smoking and/or vaping, and methods of promoting a reduction in various addictions, such as smoking and/or vaping, uses of cytisine as an addiction cessation treatment, and dosage regimens for the foregoing are provided.

PRIORITY CLAIM

This application is a divisional of U.S. patent application Ser. No.16/993,522, filed on Aug. 14, 2020, which claims priority to U.S.Provisional Application No. 62/988,890 filed on Mar. 12, 2020 and U.S.Provisional Application No. 62/899,637 filed on Sep. 12, 2019, theentire contents of each of which are incorporated herein by referenceand relied upon.

BACKGROUND

Nicotine is an addictive substance that is rapidly absorbed duringcigarette smoking. The drug distributes quickly and is thought tointeract with neuronal nicotinic acetylcholine receptors (nAChRs) in thecentral nervous system (CNS). Nicotine addiction results, at least inpart, from this interaction. Although many smokers attempt to ceasesmoking, few succeed without pharmacological supportive treatment.

Tobacco smoking contributes to some 7 million premature deaths each yearworldwide. Smoking is highly addictive, with more than 95% of unaidedattempts at cessation failing to last 6 months. It has been estimatedthat for every year that a person delays stopping smoking beyond his orher mid-30s, that person loses 3 months of life expectancy. The WorldHealth Organization's Framework Convention on Tobacco Control identifiesevidence-based approaches to promote smoking cessation, which includemass-media campaigns, tax increases on tobacco, and help for smokerswanting to stop.

The pharmacotherapies currently available in the U.S. and Western Europeto help smokers stop include nicotine replacement therapy (NRT) and twonon-nicotine containing medications: bupropion (Zyban®,Glaxo-SmithKline) and varenicline (Chantix®/Champix®, Pfizer). NRT andbupropion appear to have about equal efficacy. Varenicline is moreeffective than single NRT and bupropion, although combination NRT iscomparable in efficacy.

(−)-Cytisine (cytisinicline; commonly referred to simply as cytisine) isa plant-based alkaloid isolated from seeds of Cytisus laburnum L.(Golden chain). References herein to cytisine refer to (−)-cytisine,cytisinicline.

Cytisine's mechanism of action has assisted basic pharmacologists inunderstanding the complex pharmacology of the various subtypes of thenicotinic acetylcholine receptor. These studies have shown that bothnicotine and cytisine bind strongly and preferentially to alpha4, beta2(α₄β₂) receptors that mediate the release of dopamine in the shell ofthe nucleus accumbens and elsewhere. This receptor subtype has beenimplicated in the development and maintenance of nicotine dependence andwas the primary target for the drug varenicline, referred to above.

Tabex®, containing the active substance cytisine, has been licensed andmarketed in Central and Eastern Europe for several decades by SopharmaPLC (Sophia, Bulgaria).

A need exists for nicotine addiction treatments with patient-friendlyregimens that are less costly, more effective, have an improved safetyprofile, and/or can more successfully treat individuals who have failedto quit nicotine using the known treatments.

SUMMARY

In one aspect, provided herein is a method of treating of nicotineaddiction in a subject, comprising administering cytisine in equaldosage amounts two times per day (“bid” or “BID”) or three times per day(“tid” or “TID”) to a subject in need thereof.

In another aspect, provided herein is a method of treating nicotineaddiction, promoting cessation of smoking, and/or promoting a reductionin smoking in a subject in need thereof, the method comprisingadministering cytisine provided in a unit dose of 3.0 mg or 1.5 mg ofcytisine three times daily to the subject.

In still another aspect, provided herein is a method of treatingnicotine addiction in a subject, comprising administering cytisine at adose of either 1.5 mg or 3.0 mg of cytisine three times daily to asubject in need thereof.

In still another aspect, provided herein is a method of treatingnicotine dependence in a subject, comprising administering cytisine at adose of either 1.5 mg or 3.0 mg of cytisine three times daily to asubject in need thereof.

In still yet another aspect, provided herein is a method of treatingnicotine addiction in a subject, comprising administering cytisine to asubject in need thereof, wherein the subject is a refractory patient whohas failed treatment with one or more nicotine addiction treatments.

In yet another aspect, provided herein is a method of preventing smokingrelapse in a subject in need thereof, the method comprisingadministering cytisine provided in a unit dose of (a) two tablets, eachtablet either containing 1.5 mg or 3.0 mg of cytisine, (b) a singletablet either containing 1.5 mg or 3.0 mg of cytisine, or (c) threetablets, each tablet containing 1.0 mg of cytisine, three times daily tothe subject.

In a further aspect, provided herein is a method of preventing smokingrelapse in a subject in need thereof, the method comprisingadministering cytisine to the subject, wherein the subject is arefractory patient who has failed treatment with one or more smokingcessation treatments selected from the group consisting of NRT,administration of bupropion, administration of varenicline, electroniccigarettes (e-cigarettes), and vaping.

In one embodiment, each of the three daily administrations occurmorning, noon, and evening, respectively, or in approximately intervalsof 4-5 hours. In one embodiment, the administration occurs for a periodof at least about 6 weeks, at least about 12 weeks, at least about 24weeks or indefinitely. In another embodiment, the administration occursfor a period of at least about 6 weeks or at least about 12 weeks orrepeated for 6-12 weeks indefinitely.

In some embodiments, cytisine is provided in a unit dose of about 1.0 mgto about 6.0 mg of cytisine one to six times daily to a subject in needthereof. In some embodiments, cytisine is provided in a unit dose ofabout 1.0 mg to about 6.0 mg of cytisine three to six times daily to asubject in need thereof. In some embodiments, cytisine is provided in aunit dose of 1.5 mg of cytisine three times daily to a subject in needthereof. In some embodiments, cytisine is provided in a unit dose of 1.5mg of cytisine six times daily to a subject in need thereof. In someembodiments, cytisine is provided in a unit dose of 3.0 mg of cytisinethree times daily to a subject in need thereof. In some embodiments,cytisine is provided in a unit dose of 3.0 mg of cytisine six timesdaily to a subject in need thereof.

In some embodiments, the cytisine is administered in one or more unitdoses. In some embodiments, each unit dose (e.g., a tablet or a capsule)of cytisine comprises 1.0 mg of cytisine. In some embodiments, each unitdose (e.g., a tablet or a capsule) of cytisine comprises 1.5 mg ofcytisine. In some embodiments, the unit dose of cytisine comprises 3.0mg of cytisine. In some embodiments, each unit dose is a tablet, forexample, a compressed, film coated tablet.

In some embodiments, the subject is a refractory patient who has failedtreatment with one or more nicotine addiction treatments. In someembodiments, the subject is a refractory patient who has failedtreatment with two or more nicotine addiction treatments. In someembodiments, the nicotine addiction treatments are selected from NRT,administration of bupropion, administration of varenicline, electroniccigarettes, vaping, and a combination thereof.

In some embodiments, the subject smoked ten or more cigarettes per dayprior to the administration of cytisine. In some embodiments, thesubject has expired air carbon monoxide (CO) concentration of about 10parts per million (ppm) or greater prior to the administration ofcytisine. In some embodiments, the subject (a) smoked ten or morecigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

In some embodiments, the subject experiences no adverse events afterreceiving the cytisine treatment. In some embodiments, the adverse eventis selected from the group consisting of an upper respiratory tractinfection (URTI), abnormal dreams, nausea, insomnia, headache, fatigue,and constipation.

In some embodiments, the method further comprises providing behavioralsupport to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of dosing schedules according to the study designof Example 1 in accordance with the present technology.

FIG. 2 is a schematic of the study design of Example 1 in accordancewith the present technology.

FIG. 3 is a schematic of the dosing strengths, schedules, and durationaccording to the study design of Example 1 in accordance with thepresent technology.

FIG. 4 is a schematic showing the subject population dispositionaccording to the study of Example 1 in accordance with the presenttechnology.

FIG. 5 is a representative graph depicting a number of cigarettes smokedper treatment arm by day of treatment according to the study of Example1 in accordance with the present technology.

FIG. 6 is a representative graph depicting a reduction in cigarettessmoked versus expired CO in the subject population of Example 1 inaccordance with the present technology.

FIG. 7 is a representative graph depicting a comparison between quitrates after 4 weeks of abstinence compared to a quit rate duringcontinuous abstinence (weeks 5-8) in the subject population of Example 1in accordance with the present technology.

FIG. 8 is a representative graph depicting a comparison between the quitrates between 3.0 mg three times per day (TID) and placebo after a4-week abstinence and during continuous abstinence (Weeks 5-8).

FIG. 9 is a representative plot depicting the expired CO levels in partsper million for the pooled placebo, TID 1.5 mg, TID, 3.0 mg, commercialdosing titration schedule (COM) with 1.5 mg, and COM with 3.0 mgtreatment arms at the screening visit, at Week 4, and at Week 8 inaccordance with the present technology.

FIG. 10 is a representative plot depicting the serum cotinine levels forthe pooled placebo, TID 1.5 mg, TID 3.0 mg, COM 1.5 mg, and COM 3.0 mgat the screening visit, at Week 4, and at Week 8 in accordance with thepresent technology.

FIGS. 11A-11B are representative plots depicting a comparison betweenthe group homogeneity for the percentage of expected cigarettes smoked(Cigarette Score) compared between COM 0 mg and TID 0 mg, and betweenTID 0 mg and TID 3.0 mg in accordance with the present technology.

FIG. 12 is a schematic of the study design for comparing cytisinicline(cytisine) and Chantix® in accordance with the present technology.

FIG. 13 is a representative graph depicting the CO confirmed quit ratesbetween 3.0 mg of cytisinicline and 3.0 mg of Chantix® at 4 weeks and at12 weeks of treatment in accordance with the present technology.

FIG. 14 is a representative plot comparing the odds ratio ofcytisinicline and Chantix® at 4 weeks, end of treatment, and 4 weeks offtreatment in accordance with the present technology.

FIG. 15 is a representative plot comparing the odds ratio ofcytisinicline at 4 weeks, end of treatment, and 4 weeks off treatment tocurrent products in accordance with the present technology.

FIG. 16 is a representative plot depicting the interaction between the3.0 mg TID arm and the BMI stratifier in accordance with the presenttechnology.

FIG. 17 is a representative plot depicting an assessment usingparallelism between the arms of the straight-line relationships betweenthe Cigarette Score and the baseline mean number of cigarettes inaccordance with the present technology.

FIG. 18 is a representative plot depicting Effect Modifier Analyses(EMAs) for Cigarette Score across clinical sites for cytisine 1.5 mg TIDcompared to pooled placebo in accordance with the present technology.

FIG. 19 is a representative plot depicting EMAs for Cigarette Scoreacross clinical sites for cytisine 3.0 mg TID compared to pooled placeboin accordance with the present technology.

FIG. 20 is a representative plot depicting EMAs for Cigarette Scoreacross clinical sites for cytisine 1.5 mg COM compared to pooled placeboin accordance with the present technology.

FIG. 21 is a representative plot depicting EMAs for Cigarette Scoreacross clinical sites for cytisine 3.0 mg COM compared to pooled placeboin accordance with the present technology.

FIG. 22 is a representative plot depicting EMAs for continued 4-weekabstinence through Week 5 to Week 8, confirmed by expired CO of <10 ppm(Cess/W5-8/CO Success) across clinical sites for cytisine 1.5 mg TIDcompared to pooled placebo in accordance with the present technology.

FIG. 23 is a representative plot depicting EMAs for continued 4-weekabstinence through Week 5 to Week 8, confirmed by expired CO of <10 ppm(Cess/W5-8/CO Success) across clinical sites for cytisine 3.0 mg TIDcompared to pooled placebo in accordance with the present technology.

FIG. 24 is a representative plot depicting EMAs for continued 4-weekabstinence through Week 5 to Week 8, confirmed by expired CO of <10 ppm(Cess/W5-8/CO Success) across clinical sites for cytisine 1.5 mg COMcompared to pooled placebo in accordance with the present technology.

FIG. 25 is a representative plot depicting EMAs for continued 4-weekabstinence through Week 5 to Week 8, confirmed by expired CO of <10 ppm(Cess/W5-8/CO Success) across clinical sites for cytisine 3.0 mg COMcompared to pooled placebo in accordance with the present technology.

FIG. 26 is a representative plot depicting EMAs for Cigarette Scoreacross baseline (race, Hispanic, sex, age (M), age (T), strat BMI, smokeHx Dur (y) (M), smoke Hx Dur (y) (T), smoke Hx Dur (y) (Q), >2 Quit Hx,Screen Mean Cigs/d (M)) attributes for cytisine 3.0 mg TID compared topooled placebo in accordance with the present technology.

FIG. 27 is a representative plot depicting EMAs for continued 4-weekabstinence through Week 5 to Week 8, confirmed by expired CO of <10 ppm(Cess/W5-8/CO Success) across baseline attributes (race, Hispanic, sex,age (M), age (T), strat BMI, smoke Hx Dur (y) (M), smoke Hx Dur (y) (T),smoke Hx Dur (y) (Q), >2 Quit Hx, Screen Mean Cigs/d (M)) for cytisine3.0 mg TID compared to pooled placebo in accordance with the presenttechnology.

FIG. 28 is a representative plot depicting EMAs for Cigarette Scoreacross prior anti-smoking interventions (>2 Quit Tx, Chantix® Hx, Zyban®Hx, Vape Hx, NRT Hx, Chantix® (most recent), Zyban® (most recent), Vape(most recent), and NRT (most recent) for cytisine 3.0 mg TID) comparedto pooled placebo in accordance with the present technology.

FIG. 29 is a representative plot depicting EMAs for continued 4-weekabstinence through Week 5 to Week 8, confirmed by expired CO of <10 ppm(Cess/W5-8/CO Success) across prior anti-smoking interventions (>2 QuitTx, Chantix® Hx, Zyban® Hx, Vape Hx, NRT Hx, Chantix® (most recent),Zyban® (most recent), Vape (most recent), and NRT (most recent)) forcytisine 3.0 mg TID compared to pooled placebo in accordance with thepresent technology.

FIG. 30 is a representative plot depicting EMAs for Cigarette Scoreacross baseline laboratory markers (NMR, CO, cotinine) for cytisine 3.0mg TID compared to pooled placebo in accordance with the presenttechnology.

FIG. 31 is a representative plot depicting EMAs for continued 4-weekabstinence through Week 5 to Week 8, confirmed by expired CO of <10 ppm(Cess/W5-8/CO Success) across baseline laboratory markers (NMR, CO,cotinine) for cytisine 3.0 mg TID compared to pooled placebo inaccordance with the present technology.

FIG. 32 is a representative graph depicting tipping point analysis forcontinued 4-week abstinence through Week 5 to Week 8, confirmed byexpired CO of <10 ppm (Cess/W5-8/CO Success) for cytisine 3.0 mg TID armcompared to the pooled placebo arm in accordance with the presenttechnology.

FIG. 33 is a schematic of the study design of Example 2 in accordancewith the present technology.

DETAILED DESCRIPTION

While the present disclosure is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any manner. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

The use of numerical values in the various quantitative values specifiedin this application, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about.” It is to beunderstood, although not always explicitly stated, that all numericaldesignations are preceded by the term “about.” It is to be understoodthat such range format is used for convenience and brevity and should beunderstood flexibly to include numerical values explicitly specified aslimits of a range, but also to include all individual numerical valuesor sub-ranges encompassed within that range as if each numerical valueand sub-range is explicitly specified. For example, a ratio in the rangeof about 1 to about 200 should be understood to include the explicitlyrecited limits of about 1 and about 200, but also to include individualratios such as about 2, about 3, and about 4, and sub-ranges such asabout 10 to about 50, about 20 to about 100, and so forth. It also is tobe understood, although not always explicitly stated, that the reagentsdescribed herein are merely exemplary and that equivalents of such areknown in the art.

The term “about,” as used herein when referring to a measurable valuesuch as an amount or concentration and the like, is meant to encompassvariations of 20%, 10%, 5%, 1%, 0.5% or even 0.1% of the specifiedamount.

Also, the disclosure of ranges is intended as a continuous range,including every value between the minimum and maximum values recited, aswell as any ranges that can be formed by such values. Also disclosedherein are any and all ratios (and ranges of any such ratios) that canbe formed by dividing a disclosed numeric value into any other disclosednumeric value. Accordingly, the skilled person will appreciate that manysuch ratios, ranges, and ranges of ratios can be unambiguously derivedfrom the numerical values presented herein and in all instances, suchratios, ranges, and ranges of ratios represent various embodiments ofthe present disclosure.

The phrase “statistical significance,” as used herein refers to a resultfrom data generated by testing or experimentation, is not likely tooccur randomly or by chance, but is instead likely to be attributable toa specific cause. Statistical significance is evaluated from acalculated probability (p-value), where the p-value is a function of themeans and standard deviations of the data samples and indicates theprobability under which a statistical result occurred by chance or bysampling error. A result is considered statistically significant if thep-value is 0.05 or less, corresponding to a confidence level of 95%.

“Comprising” or “comprises” is intended to mean that the compositionsand methods include the recited elements, but not excluding others.“Consisting essentially of” when used to define compositions andmethods, shall mean excluding other elements of any essentialsignificance to the combination for the stated purpose. Thus, acomposition consisting essentially of the elements as defined hereinwould not exclude other materials or steps that do not materially affectthe basic and novel characteristic(s) of the claimed invention.“Consisting of” shall mean excluding more than trace elements of otheringredients and substantial method steps. Embodiments defined by each ofthese transition terms are within the scope of this invention.

The phrase “control subject,” as used herein refers to any subject usedas a basis for comparison to the test subject. A control subjectincludes, but is not limited to, any subject who has not beenadministered the composition, administered a composition other than thetest composition (e.g., 1.5 mg of cytisine three times per day or 3.0 mgof cytisine three times per day), or administered a placebo.

The term “treatment” in relation to a given disease or disorder,includes, but is not limited to, inhibiting the disease or disorder, forexample, arresting the development of the disease or disorder; relievingthe disease or disorder, for example, causing regression of the diseaseor disorder; or relieving a condition caused by or resulting from thedisease or disorder, for example, relieving or treating symptoms of thedisease or disorder. The term “prevention” in relation to a givendisease or disorder means: preventing the onset of disease developmentif none had occurred, preventing the disease or disorder from occurringin a subject that may be predisposed to the disorder or disease but hasnot yet been diagnosed as having the disorder or disease, and/orpreventing further disease/disorder development if already present.

“Vaping” refers to the act of a subject inhaling vapor created by adevice from a solution carried in a cartridge or a chamber. In someembodiments, the device is electronic and simulates smoking. Vapingdevices can include, but are not limited, to a power source, anatomizer, and the cartridge or chamber. In some embodiments, vapingrefers to consumption of ejuice or vaping activity, such as taking orotherwise consuming puffs of vapor from the vaping device, performing avaping session with the vaping device, or otherwise using the vapingdevice to ingest vapor. In another embodiment, vaping refers toconsumption of ejuice. In an alternative embodiment, vaping refers toconsumption of ejuice or taking or otherwise consuming puffs of vaporfrom the vaping device. In yet another embodiment, vaping refers tovaping activity. In other embodiments, vaping refers to taking orotherwise consuming puffs of vapor from the vaping device, performing avaping session with the vaping device, or otherwise using the vapingdevice to ingest vapor. In further embodiments, vaping refers to takingor otherwise consuming puffs of vapor from the vaping device orotherwise using the vaping device to ingest vapor. In still furtherembodiments, vaping refers to using the vaping device to ingest vapor.

As used herein, the terms “reduction in vaping,” “reduced vaping,” and“reduces vaping” refers to decreasing a frequency or amount of vapingper hour, per day, per week, per month, or per year, such as reducing anamount of ejuice consumed, a reduction in a number or a frequency ofpuffs of vapor taken or otherwise consumed from the vaping device, areduction in a number or a frequency of vaping session performed withthe vaping device, or a reduction in use of the vaping device to ingestvapor.

As used herein, the term “adverse event” (AE) refers to any untowardmedical occurrence in a subject administered a composition and whichdoes not necessarily have attribution with the treatment. An AE cantherefore be any unfavorable and unintended sign (including an abnormallaboratory finding), symptom, or disease temporally associated with theuse of the composition, whether or not considered related to thecomposition.

As used herein, the term “adverse drug reaction” refers to any untowardand unintended responses to the administered composition. The term“response to the composition” means that attribution has at least areasonable possibility (i.e., the relationship cannot be ruled out andis judged by the investigator as at least possible) (see definitionbelow).

The terms “serious adverse event” (SAE) and “serious adverse reaction”(SAR) refer to an AE that results in at least one of the following AEs:death, life-threatening, requires hospitalization or prolongs asubject's existing hospitalization, results in persistent or significantdisability or incapacity, results in a congenital abnormality or birthdefect, or is an important medical event which requires medicalintervention to prevent any of the foregoing outcomes.

As used herein, the term “suspected unexpected serious adversereactions” (SUSARs) are AEs which are serious, unexpected, and there isat least a reasonable possibility that there is attribution between theevent and the composition. Important medical events are those which maynot be immediately life-threatening but may jeopardize the subject andmay require intervention to prevent one of the other serious outcomeslisted above. Examples of such events are intensive treatment in anemergency room or at home for allergic bronchospasm, or blood dyscrasiasor convulsions that do not result in hospitalization. The term“life-threatening” refers to an event in which the subject was at riskof death at the time of the event; it does not refer to an event whichhypothetically might have caused death if it were more severe. Forexample, drug-induced hepatitis that resolves without evidence ofhepatic failure would not be considered life threatening even thoughdrug-induced hepatitis can be fatal. Inpatient hospitalization orprolongation of existing hospitalization means that hospital inpatientadmission and/or prolongation of hospital stay were required fortreatment of AE or occurred as a consequence of the event. It does notrefer to pre-planned elective hospital admission for treatment of apre-existing condition that has not significantly worsened, or todiagnostic procedures.

The terms “cytisine-treated arm,” “active arms,” “treatment arm,”“active treatment arm,” and “investigational arm” are usedinterchangeably throughout and refer to subjects administered acomposition comprising cytisine.

List of abbreviations: ADR, Adverse Drug Reaction; AE, Adverse Event;ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; BMI,Body Mass Index; Cmax, Maximum Observed Plasma Concentration; CrCl,Creatinine Clearance; CRF, Case Report Form; DSM, Data Safety Monitor;ECG, Electrocardiogram; GCP, Good Clinical Practice; ICH, InternationalConference on Harmonization; IMP, Investigational Medicinal Product (forthis protocol, indicates cytisinicline 3.0 mg film coated tablet);MedDRA, Medical Dictionary for Regulatory Activities; SAE, SeriousAdverse Event; SAR, Serious Adverse Reaction; SmPC, Summary of ProductCharacteristics; SOC, MedDRA System Organ Class; SUSAR, SuspectedUnexpected Serious Adverse Reaction; Tmax, Time to Maximum ObservedConcentration; UADR, Unexpected Adverse Drug Reaction; UAE, UnexpectedAdverse Event; ULN, Upper Limit of Normal.

Compositions

A composition for use in methods of the disclosure comprises cytisine ora pharmaceutically acceptable derivative, conjugate, or salt thereof, ormixtures of any of the foregoing, collectively referred to herein as“cytisine.” The term “pharmaceutically acceptable” in the presentcontext means that the substance in question does not produceunacceptable toxicity to the subject or interaction with othercomponents of the composition. Cytisine, (−)-cytisine, and cytisiniclineare referenced interchangeably.

Any suitable cytisine pharmaceutical composition or formulation can beused in the methods described herein. In some embodiments, cytisine canbe formulated in tablet form, for example, as compressed film-coatedtablets for oral administration.

A composition for use in accordance with the disclosure can beformulated as one or more dosage units. The terms “dose unit” and“dosage unit” herein refer to a portion of a pharmaceutical compositionthat contains an amount of a therapeutic agent suitable for a singleadministration to provide a therapeutic effect. Such dosage units may beadministered one to a plurality (i.e., 1 to about 10, 1 to 8, 1 to 6, 1to 4, 1 to 3, or 1 to 2) of times per day, or as many times as needed toelicit a therapeutic response.

The unit dose can comprise a single tablet, such as a tablet containing3.0 mg of cytisine, or it can comprise two or more tablets whichtogether contain the unit dose (e.g., 3.0 mg of cytisine). For example,the unit dose of 3.0 mg can comprise two tablets, each containing 1.5 mgof cytisine, such as two Tabex® tablets. Each Tabex® tablet is typicallyformulated as a compressed film-coated tablet containing 1.5 mg ofcytisine in a single tablet together with a number of tablet-formingexcipients (calcium sulfate, cellulose powder, colloidal silica,magnesium stearate) and coated with a colored film-coat, includingpolyvinyl alcohol, titanium dioxide, and iron oxides. As anotherexample, the unit dose of 3.0 mg can comprise three tablets, eachcontaining 1.0 mg of cytisine, such as three tablets formulated at leastsimilarly to the Tabex® tablets.

Alternatively, the cytisine may be formulated in a capsule or anothervehicle for oral administration and are orally deliverable; or in acomposition for nasal or topical administration. The terms “orallydeliverable” or “oral administration” herein include any form ofdelivery of a therapeutic agent or a composition thereof to a subjectwherein the agent or composition is placed in the mouth of the subject,whether or not the agent or composition is swallowed. Thus, “oraladministration” includes buccal and sublingual, as well as esophagealadministration.

The tablets and other dosage forms (hereinafter all referred to as“compositions”) can contain one or more excipients, such as those commonin the art. Excipients that can be employed in the compositions include,for example, fillers, disintegrants, preserving agents, lubricants, andwetting agents.

Examples of fillers that can be used include lactose (for example,either anhydrous or monohydrate), cellulose, starch (for example, cornand/or wheat starch), calcium phosphates, calcium sulfates, andmannitol.

Preserving agents prevent bacterial or fungal contamination of theformulation and include various antibacterial and antifungal agents,such as parabens, chlorobutanol, phenol, and sorbic acid.

Suitable lubricants include stearic acid and its salts. One example of alubricant for use in the compositions of the disclosure is magnesiumstearate.

The pharmaceutical compositions can further comprise sweetening,flavoring, or coloring agents.

In some embodiments, the placebo is a tablet which comprises the same,substantially the same, similar, or substantially similar non-active(e.g., cytisine) components to the test composition. In theseembodiments, the placebo comprises at least the same, substantially thesame, similar, or substantially similar excipients, fillers, preservingagents, lubricants, sweetening, flavoring, and/or coloring agents as thetest composition, as well as at least one other non-active component,such as cellulose. In some embodiments, the placebo tablet and the testcomposition tablet are the same or substantially the same weight, size,shape, color, and/or are contained in the same or substantially the samepackaging.

A person skilled in the art will be well aware of suitable fillers,preserving agents, and lubricants other than those specificallymentioned above, as well as suitable sweetening, flavoring, and coloringagents, and other additives. The pharmaceutical compositions of cytisineuseful in the methods of the disclosure can comprise a coating, forexample, a film coating, and can be coated according to any method knownin the art, for example, using collidone, shellac, gum arabic, talc,titanium dioxide, or sugar.

The pharmaceutical compositions comprising cytisine can be prepared byany suitable method. For example, capsules can be prepared by mixingcytisine with one or more inert carriers such as lactose or sorbitol andpacking into gelatin capsules. Tablets can be made by known compressionmethods.

In one embodiment, compositions of the disclosure, upon storage in aclosed container maintained at room temperature, refrigerated (e.g.,about 5° C. to about −10° C.) temperature, or frozen for a period ofabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at leastabout 90%, at least about 95%, at least about 97.5%, or at least about99% of the active ingredient(s) originally present therein.

Methods

The disclosure provides treating a nicotine addiction or a nicotinedependence in a subject in need thereof, comprising administering thesubject an effective amount of cytisine. In some embodiments, themethods of treating a nicotine addiction or a nicotine dependenceinclude preventing smoking relapse and/or promoting cessation of orreduction in smoking in the subject in need thereof.

In some embodiments, the disclosure provides methods of treatingnicotine addiction or a nicotine dependence in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of cytisine. In some embodiments, present disclosurerelates to methods for preventing smoking relapse in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of cytisine. In another embodiment, the disclosureprovides methods of promoting cessation of smoking in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of cytisine. In some embodiments, the disclosureprovides methods for promoting a reduction in smoking of a subject inneed thereof, comprising administering to the subject an effectiveamount of cytisine. In some embodiments, the disclosure provides methodsof treating nicotine addiction or a nicotine dependence in a subject inneed thereof, wherein the nicotine addiction or a nicotine dependence isin the form of cigarettes, smokeless tobacco, snus, electroniccigarettes (e-cigs), vapes such as vaping using a vaping device, and/orhookah. In some embodiments, the vaping device includes a liquidcomprising nicotine, for example, about 1 mg/ml nicotine to about 12mg/ml nicotine or greater than about 13 mg/ml nicotine. Any patient withnicotine addiction or a nicotine dependence can be treated by themethods disclosed herein.

In additional embodiments, the disclosure provides methods of treatingand/or preventing an addiction or a dependence in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of cytisine. Without intending to be bound by anyparticular theory, it is thought that cytisine interacts with thedopamine neurotransmitter release cycle as a partial agonist ofnicotinic acetylcholine receptors (nAChRs) and is useful for treatingand/or preventing a plurality of addictions or plurality of dependencesin a subject in need thereof. Non-limiting examples of addictions anddependencies that are thought to be treated and/or prevented byadministration of cytisine includes addictions and/or dependencies tosubstances, compounds, and/or behaviors that may involve the dopamineneurotransmitter release cycle. Exemplary substances, compounds, and/orbehaviors includes, but is not limited to, marijuana, cannabis,tetrahydrocannabinol (THC), cannabidiol (CBD), alcohol, opioids andother painkillers, cocaine, eating, gambling, sex, heroin,benzodiazepines, barbiturates, stimulants, and inhalants. In furtherembodiments, the disclosure provides methods of promoting cessation ofthe addiction or the dependence in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount ofcytisine. In some embodiments, the disclosure provides methods forpromoting a reduction in a subject's addiction and/or dependence,comprising administering to the subject an effective amount of cytisine.The compositions and methods described herein with respect to smoking,vaping, and nicotine can be used to treat, prevent, and/or reduceaddiction or dependence in the subject in need thereof, such as anysubject having an addiction or a dependence involving the dopamineneurotransmitter release cycle.

In further embodiments, the methods of treating a nicotine addiction ora nicotine dependence include preventing vaping relapse and/or promotingcessation of or reduction in vaping in the subject in need thereof. Insome embodiments, the present disclosure relates to methods forpreventing vaping relapse in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount ofcytisine. In another embodiment, the disclosure provides methods ofpromoting cessation of vaping in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount ofcytisine. In some embodiments, the disclosure provides methods forpromoting a reduction in vaping of a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount ofcytisine.

In some embodiments, provided herein is a method of treating of nicotineaddiction or a nicotine dependence in a subject, comprisingadministering cytisine in equal dosage amounts two times per day (“bid”or “BID”) or three times per day (“tid” or “TID”) to a subject in needthereof. In one embodiment, each of the two daily administrations occurmorning and evening, respectively. In another embodiment, each of thetwo daily administrations occur in approximate intervals of 10-12 hours.In yet another embodiment, each of the three daily administrations occurmorning, noon, and evening, respectively. In another embodiment, each ofthe three daily administrations occur in approximate intervals of 4-5hours. In yet another embodiment, each of the three dailyadministrations occur in approximate intervals of 4 hours, 5 hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, or more. In one embodiment,the administration occurs for a period of at least about 6 weeks, atleast about 12 weeks, at least about 24 weeks, or indefinitely. In thisembodiment, the administration can include BID or TID for any period ofdays or weeks during the administration. For example, in theseembodiments, the entire period of administration can be BID or TID. Asanother example, in these embodiments, at least a portion of theadministration can be BID or TID, such as at least about one day, atleast about three days, at least about one week, at least about twoweeks, at least about four weeks, at least about 12 weeks. As yetanother example, in these embodiments, the BID or TID administration canoccur in any order, such as Day 1 can be BID or TID, Day 2 can be BID orTID, Day 3 can be BID or TID, and so on for the period ofadministration.

In some embodiments, the administration occurs independent of whetherthe subject is in a fed or fasted state. For example, the administrationcan occur simultaneously with food, concurrently with food, any amountof time before the subject ingests food, or any amount of time after thesubject ingests food. Without intending to be limited to any particulartheory, it is not thought that food (or a fed state or a fasted state)impacts the bioavailability of cytisine which can be determined by anoverall body absorption or overall bioavailability of cytisine in thesubject.

In some embodiments, the TID dose is 1 mg, 1.5 mg, 2 mg, 2.5 mg, or 3.0mg of cytisine. In some embodiments, the TID dose is 1 mg, regardless ofhow the dose is divided. For example, each TID dose could be given intwo 0.5 mg strength tablets administered 3 times per day or in one 1 mgtablet administered three times per day, or any other possibility. Insome embodiments, the TID dose is 1.0 mg, regardless of how the dose isdivided among dosage units. In some embodiments, the TID dose is 1.5 mg,regardless of how the dose is divided among dosage units. In someembodiments, the TID dose is 2 mg, regardless of how the dose is dividedamong dosage units. In yet another embodiment, the TID dose is 2.5 mg,regardless of how the dose is divided among dosage units. In someembodiments, the TID dose is 3.0 mg, regardless of how the dose isdivided among dosage units.

In some embodiments, the subject experiences no adverse events relatedto the cytisine treatment. Adverse events can be mild (e.g, nointerference with activity), moderate (some interference with activitybut requiring no or minimal medical intervention), or severe (preventsdaily activity and requires medical intervention). Non-limiting examplesof adverse events include an upper respiratory tract infection (URTI),abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.In other embodiments, the subject experiences two or fewer adverseevents related to the cytisine treatment, such as, an increase in theoccurrence of nausea, abnormal dreams, insomnia, headache, and/or URTIin a subject from about 0% to about 10%, for example, about 0%, about1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about8%, about 9%, or about 10%. In some embodiments, the subject experiencesno adverse events as compared to a subject administered a nicotinereplacement therapy (NRT), bupropion, varenicline, electroniccigarettes, vaping, and/or combination thereof.

In some embodiments, the subject experiences nicotine addiction or anicotine dependence by smoking cigarettes, ingesting smokeless tobaccoand/or snus, using electronic cigarettes (e-cigs) and/or vapes, and/orusing hookah daily, such as a per unit consumption of nicotine per day.In some embodiments, the subject having nicotine addiction or a nicotinedependence consumes about 0 to about 100 units of nicotine per day. Forexample, a single cigarette may be a unit of nicotine and the subjecthaving the nicotine addiction or a nicotine dependence smokes about 0cigarettes per day to about 100 cigarettes per day, about 5 cigarettesper day to about 75 cigarettes per day, about 5 cigarettes per day toabout 50 cigarettes per day, about 5 cigarettes per day to about 25cigarettes per day, about 10 cigarettes per day to about 50 cigarettesper day, about 20 cigarettes per day to about 50 cigarettes per day,about 25 cigarettes per day to about 75 cigarettes per day, about 25cigarettes per day to about 50 cigarettes per day, for example, about 0cigarettes per day, about 1 cigarette per day, about 2 cigarettes perday, about 3 cigarettes per day, about 4 cigarettes per day, about 5cigarettes per day, about 6 cigarettes per day, about 7 cigarettes perday, about 8 cigarettes per day, about 9 cigarettes per day, about 10cigarettes per day, about 11 cigarettes per day, about 12 cigarettes perday, about 13 cigarettes per day, about 14 cigarettes per day, about 15cigarettes per day, about 16 cigarettes per day, about 17 cigarettes perday, about 18 cigarettes per day, about 19 cigarettes per day, about 20cigarettes per day, about 25 cigarettes per day, about 30 cigarettes perday, about 35 cigarettes per day, about 40 cigarettes per day, about 45cigarettes per day, about 50 cigarettes per day, about 55 cigarettes perday, about 60 cigarettes per day, about 65 cigarettes per day, about 70cigarettes per day, about 75 cigarettes per day, about 80 cigarettes perday, about 85 cigarettes per day, about 90 cigarettes per day, or about100 cigarettes per day. In other examples, units of nicotine alsoinclude ingesting smokeless tobacco and/or snus, using electroniccigarettes (e-cigs) and/or vapes (e.g., vaping), and/or using hookahinstead of or in combination with cigarettes daily.

In some embodiments, administration of cytisine reduces the number ofunits of nicotine a subject ingests per day, such as a number ofcigarettes a subject smokes per day. In some embodiments, the methods ofthe present technology reduce a percentage of cigarettes smoked by thesubject by at least about 60%, at least about 65%, at least about 70%,at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, or at least about 100% as compared to acontrol subject, placebo control, and/or baseline after treatment with1.0 mg TID, 1.5 mg TID, or 3.0 mg TID of cytisine.

In some embodiments, the administration of cytisine increases abstinencein the subject after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mgTID of cytisine. In these embodiments, the subject has increasedabstinence of about 5% to about 30%, for example, about 5% to about 15%,about 5% to about 10%, about 5% to about <10%, about 10% to about 25%,about 15% to about 20%, about 20% to about 30%, or about 25% to about<30%, about 5% to about 100%, about 5% to about 75%, about 5% to about50%, about 25% to about 75%, about 25% to about 50%, about 30% to about50%, about 30% to about 50%, about 30% to about 75%, about 30% to about<100%, or about 30% to about 100%, such as at least about 10%, at leastabout 15%, at least about 20%, at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, at leastabout 50%, or at least about 55% following cytisine treatment relativeto an abstinence achieved without cytisine treatment. In someembodiments, abstinence is a period of abstinence, such as about a 2week abstinence, about a 3 week abstinence, about a 4 week abstinence,about a 5 week abstinence, about a 6 week abstinence, about a 7 weekabstinence, about an 8 week abstinence, about a 12 week abstinence,about a 16 week abstinence, about a 20 week abstinence, about a 24 weekabstinence, about a 28 week abstinence, or about a 32 week abstinence.In certain embodiments, the period of abstinence is about 1 day to about4 weeks, from about 1 week to about 8 weeks, from about 2 weeks to about12 weeks, from about 4 weeks to about 24 weeks, or from about 8 weeks toabout 32 weeks.

In some embodiments, administration of cytisine increases a quit rate inthe subject after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TIDof cytisine. In these embodiments, the subject has a quit rate of about5% to about 30%, for example, about 5% to about 15%, about 5% to about10%, about 5% to about <10%, about 10% to about 25%, about 15% to about20%, about 20% to about 30%, or about 25% to about <30%, about 5% toabout 100%, about 5% to about 75%, about 5% to about 50%, about 25% toabout 75%, about 25% to about 50%, about 30% to about 50%, about 30% toabout 50%, about 30% to about 75%, about 30% to about <100%, or about30% to about 100%, such as at least about 10%, at least about 15%, atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, or atleast about 55% after a 4 week abstinence or during continuousabstinence during weeks 5-8 following cytisine treatment. In someembodiments, quit rate is determined after a period of abstinence, suchas about a 1 day abstinence, about a 3 day abstinence, about a 7 dayabstinence, about a 10 day abstinence, about a 2 week abstinence, abouta 3 week abstinence, about a 4 week abstinence, about a 5 weekabstinence, about a 6 week abstinence, about a 7 week abstinence, aboutan 8 week abstinence, about a 9 week abstinence, about a 10 weekabstinence, about an 11 week abstinence, about a 12 week abstinence,about a 16 week abstinence, about a 20 week abstinence, about a 24 weekabstinence, about a 28 week abstinence, or about a 32 week abstinence.In certain embodiments, the period of abstinence is about 1 day to about4 weeks, from about 1 week to about 8 weeks, from about 1 week to about2 weeks, from about 3 weeks to about 6 weeks, from about 2 weeks toabout 12 weeks, from about 9 weeks to about 12 weeks, from about 4 weeksto about 24 weeks, or from about 8 weeks to about 32 weeks.

In some embodiments, the subject has expired CO levels of about 0 ppm toabout 50 ppm, for example, about 10 ppm to about 40 ppm, about 10 ppm toabout 30 ppm, about 10 ppm to about <20 ppm, about 20 ppm to about 30ppm, about 20 ppm to about 40 ppm, about 20 ppm to about <50 ppm, orabout 20 ppm to about 50 ppm, for example, about 0 ppm, about 2 ppm,about 4 ppm, about 6 ppm, about 8 ppm, about 10 ppm, about 12 ppm, about14 ppm, about 16 ppm, about 18 ppm, about 20 ppm, about 22 ppm, about 24ppm, about 26 ppm, about 28 ppm, about 30 ppm, about 32 ppm, about 34ppm, about 36 ppm, about 38 ppm, about 40 ppm, about 42 ppm, about 44ppm, about 46 ppm, about 48 ppm, or about 50 ppm before treatment withcytisine. In some embodiments, administration of 1.0 mg TID, 1.5 mg TID,or 3.0 mg TID of cytisine, or treatment with 1.0 mg TID, 1.5 mg TID, or3.0 mg TID of cytisine, reduces a level of expired CO by the subject byat least about 60%, at least about 65%, at least about 70%, at leastabout 75%, at least about 80%, at least about 85%, at least about 90%,at least about 95%, or at least about 100% as compared to a controlsubject, placebo control, and/or baseline. In some embodiments, thesubject has expired CO levels of about 0 ppm to about 30 ppm, forexample, about 10 ppm to about 25 ppm, about 10 ppm to about 20 ppm,about 10 ppm to about <20 ppm, about 5 ppm to about 15 ppm, about 5 ppmto about 10 ppm, about 1 ppm to about <10 ppm, or about 10 ppm to about5 ppm, for example about 0 ppm, about 2 ppm, about 4 ppm, about 6 ppm,about 8 ppm, about 10 ppm, about 12 ppm, about 14 ppm, about 16 ppm,about 18 ppm, or about 20 ppm after treatment with cytisine.

In some embodiments, the subject has serum and/or plasma cotinine levelsof about 5 ng/mL to about 500 ng/mL, about 25 ng/mL to about 400 ng/mL,about 25 ng/mL to about 400 ng/mL, about 25 ng/mL to about 300 ng/mL,about 50 ng/mL to about 200 ng/mL, about 75 ng/mL to about 150 ng/mL,about 85 ng/mL to about 100 ng/mL, about 100 ng/mL to about 400 ng/mL,about 100 ng/mL to about 300 ng/mL, about 100 ng/mL to about 200 ng/mL,about 200 ng/mL to about 300 ng/mL, about 200 ng/mL to about 400 ng/mL,about 200 ng/mL to about <500 ng/mL, about 200 ng/mL to about 500 ng/mL,for example, about 10 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL,about 90 ng/mL, about 100 ng/mL, about 125 ng/mL, about 150 ng/mL, about175 ng/mL, about 200 ng/mL, about 225 ng/mL, about 250 ng/mL, about 275ng/mL, about 300 ng/mL, about 325 ng/mL, about 350 ng/mL, about 375ng/mL, about 400 ng/mL, about 425 ng/mL, about 450 ng/mL, about 475ng/mL, or about 500 ng/mL before treatment with cytisine. In someembodiments, administration of 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID ofcytisine, or treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mg TID ofcytisine, reduces serum and/or plasma cotinine levels in the subject byat least about 20%, at least about 25%, at least about 30%, at leastabout 35%, at least about 40%, at least about 45%, at least about 50%,at least about 55%, at least about 60%, at least about 65%, at leastabout 70%, at least about 75%, at least about 80%, at least about 85%,at least about 90%, at least about 95%, or at least about 100% ascompared to a control subject, placebo control, and/or baseline. In someembodiments, the subject has serum and/or plasma cotinine levels ofabout 0.1 ng/mL to about 20 ng/mL, about 0.1 ng/mL to about 15 ng/mL,about 0.5 ng/mL to about 10 ng/mL, about 1 ng/mL to about 10 ng/mL,about 0.5 ng/mL to about 5 ng/mL, or about 0.5 ng/mL to about 1 ng/mL,for example, about 0.1 ng/mL, about 0.5 ng/mL, about 1 ng/mL, about 1.5ng/mL, about 3 ng/mL, about 5 ng/mL, about 7 ng/mL, about 8 ng/mL, about9 ng/mL, about 10 ng/mL, about 15 ng/mL, or about 20 ng/mL aftertreatment with cytisine.

In some embodiments, administration of cytisine increases an odds ratioin the subject after treatment with 1.0 mg TID, 1.5 mg TID, or 3.0 mgTID of cytisine for 4 weeks of treatment, after 8 weeks of treatment,and 4 weeks after treatment ends. In these embodiments, the subject hasan odds ratio of about 1.1 to about 20, about 1.1 to about 15, about 1.1to about 10, about 1.1 to about 5, about 5 to about 10, about 5 to about15, about 10 to about 15, about 10 to about <20, or about 10 to about 20as compared to a control subject, placebo control, and/or baseline.

In some embodiments, the subject's vital signs, hematology and chemistrylevels, and ECG are measured prior to and/or after administration ofcytisine. In some embodiments, the subject exhibits noclinically-significant changes in vital signs, hematology and chemistrylevels, and ECG after administration of cytisine.

In some embodiments, the subject is a heavy, moderate, or light nicotineuser, such as a smoker or a vaper using nicotine can be categorized as a“heavy smoker” or “heavy vaper,” a “moderate smoker” or “moderatevaper,” or a “light smoker” or “light vaper.” For example, a “heavysmoker” as provided herein refers to a subject who reports consuming 20or more cigarettes per day. A “moderate smoker” as provided hereinrefers to a subject who reports consuming 11-19 cigarettes per day. A“light smoker” as provided herein refers to a subject who reportsconsuming 1-10 cigarettes per day. As another example, a “heavy vaper”as provided herein refers to a subject who reports performing 20 or morevaping sessions per day, consuming 20 or more puffs from a vaping deviceper day, or otherwise reports 20 or more uses of a vaping device perday. A “moderate vaper” as provided herein refers to a subject whoreports performing 11-19 vaping sessions per day, consuming 11-19 puffsfrom a vaping device per day, or otherwise reports 11-19 uses of avaping device per day. A “light vaper” as provided herein refers to asubject who reports performing 1-10 vaping sessions per day, consuming1-10 puffs from a vaping device per day, or otherwise reports 1-10 usesof a vaping device per day. In some embodiments, administration ofcytisine reduces cotinine levels in a subject identified as a heavysmoker or a heavy vaper. In some embodiments, administration of cytisinereduces cotinine levels in a subject identified as a moderate smoker ora moderate vaper. In yet another embodiment, administration of cytisinereduces cotinine levels in a subject identified as a light smoker or alight vaper.

In some embodiments, the subject has been smoking or vaping for at leastabout 1 year, at least about 5 years, at least about 10 years, at leastabout 15 years, at least about 20 years, at least about 25 years, atleast about 30 years, at least about 35 years, at least about 40 years,at least about 45 years, at least about 50 years, or more, prior toadministration of cytisine.

In some embodiments, the subject began smoking or vaping as anadolescent.

In some embodiments, the subject began smoking cigarettes or vapingbetween the ages of 10 and 19. In some embodiments, the subject begansmoking cigarettes or vaping as an adolescent and has been smokingcigarettes or vaping for at least about 20 years, at least about 25years, at least about 30 years, at least about 35 years, at least about40 years, at least about 45 years, at least about 50 years, or moreprior to administration of cytisine.

In some embodiments, the length of the administration is up to about 26weeks. In certain embodiments the length of the administration is fromabout 6 weeks to about 12 weeks, and in some embodiments, the cytisineis administered as described above for about 6 weeks.

Compared with the commercial 25-day titration schedule with unit dosesof 1.5 mg of cytisine, the percentage of smokers with continuousabstinence is surprisingly higher in the subjects treated according tothe methods disclosed herein, as demonstrated, for example, in FIG. 7.

In some embodiments, the subject is a smoker, for example, a smoker whosmokes about 3 or more cigarettes a day. In some embodiments, thesubject is a smoker who smokes about 5 or more or about 10 or morecigarettes a day. In some embodiments, the subject has measurableexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine.

In some embodiments, the subject is a refractory patient. As usedherein, a “refractory patient” or “refractory subject” is a subject whohas failed treatment with one or more nicotine addiction or nicotinedependence treatments. In some embodiments, nicotine addiction ornicotine dependence treatments include both the regulatoryagency-approved treatments and smoking cessation methods, such as vapingand behavioral support. Non-limiting examples of behavioral supportinclude behavioral support useful for reducing, preventing, or otherwisetreating anxiety, depression, and/or withdrawal symptoms. In certainembodiments, behavioral support includes counseling, diaries, wearabledevices, apps, web-based smoking cessation programs, textinginterventions, and combinations thereof. In further embodiments,behavioral support is provided to non-refractory patients, such ascontrol patients (e.g., baseline, administered a placebo, administered asmoking, vaping, or nicotine cessation medication that does not includecytisinicline). In some embodiments, the nicotine addiction or nicotinedependence treatments include FDA-approved, first-line smoking cessationmedications such as NRT, bupropion, and varenicline. Nicotinereplacement therapy can be in the form of patch, gum, lozenge, spray,and inhaler.

In some embodiments, the subject is a refractory patient who has failedtreatment with one or more nicotine addiction or nicotine dependencetreatments. For example, the subject has failed two or more treatments,three or more treatments, four or more treatments, five or moretreatments, six or more treatments, seven or more treatments, eight ormore treatments, nine or more treatments, or ten or more treatments. Insome embodiments, the subject is a refractory patient who has failednicotine addiction or nicotine dependence treatments comprising NRT,administration of bupropion, administration of varenicline, electroniccigarettes, vaping, or a combination thereof.

In some embodiments, the subject has previously attempted to quitsmoking or vaping at least 1 time, at least 2 times, at least 3 times,at least 4 times, at least 5 times, at least 6 times, at least 7 times,at least 8 times, at least 9 times, at least 10 times, or more prior toadministration of cytisine.

In some embodiments, the refractory subject has previously receivednicotine addiction and/or nicotine dependence treatment for at leastabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 11 weeks, or about 12 weeks prior to administration ofcytisine.

In one aspect, the methods comprise administering cytisine to thesubject, wherein the cytisine is provided in a unit dose of about 1.0 mgto about 5.0 mg. In certain embodiments, the unit dose of cytisine isabout 1.0 mg. In certain embodiments, the unit dose of cytisine is about1.5 mg. In certain embodiments, the unit dose of cytisine is about 3.0mg. In some embodiments, the unit dose of cytisine is administered tothe subject three to six times daily. In some embodiments, the unit doseof cytisine is administered to the subject three times per day. In someembodiments of the methods disclosed herein, the unit dose is eitherabout 1.0 mg administered three times daily, about 1.5 mg administeredthree times daily, or about 3.0 mg administered three times daily forabout 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about10 weeks, about 11 weeks, about 12 weeks, about 4 months, about 1 year,about 1.25 years, about 1.5 years, about 1.75 years, about 2 years, ormore than about 2 years. In certain embodiments, the unit dose ofcytisine is administered for up to about 2 weeks, for about 2 weeks toabout 6 weeks, for about 3 weeks to about 6 weeks, or for about 9 weeksto about 12 weeks. In some embodiments, a relapse rate is lower forsubjects administered the unit dose of cytisine for at least about 4weeks compared to subjects administered the unit dose of cytisine for atleast about 2 weeks. In other embodiments, a relapse rate is lower forsubjects administered the unit dose of cytisine for at least about 6weeks compared to subjects administered the unit dose of cytisine for atleast about 4 weeks. In further embodiments, a relapse rate is lower forsubjects administered the unit dose of cytisine for at least about 8weeks compared to subjects administered the unit dose of cytisine for atleast about 4 weeks. In still further embodiments, a relapse rate islower for subjects administered the unit dose of cytisine for at leastabout 12 weeks compared to subjects administered the unit dose ofcytisine for at least about 4 weeks.

In some embodiments, administration of cytisine to the subject resultedin a significantly better nicotine use cessation rate (smoking cessationrate or vaping succession rate), as compared to a subject administeredthe commercial 1.5 mg per unit dose titration schedule. In someembodiments, the unit dose of 3.0 mg of cytisine is administered threetimes daily for 6 weeks (e.g., the first 6 weeks) followed by placebofor 6 weeks (e.g., the second six weeks). In certain embodiments,behavioral support is provided to the subject during at least a portionof the first 6 weeks, during at least a portion of the second 6 weeks,before at least a portion of the first 6 weeks, after at least a portionof the second 6 weeks, or during a combination thereof. In someembodiments, the unit dose of 3.0 mg of cytisine is administered threetimes daily for 12 weeks. In certain embodiments, behavioral support isprovided to the subject during at least a portion of the 12 weeks,before the 12 weeks, after the 12 weeks, or a combination thereof.Thereafter, in some embodiments the subject exhibits one or more of:

(a) a reduction in units of nicotine used per day, such as cigarettessmoked per day or vaping per day, as compared to a subject who has beenadministered an NRT, a control subject, placebo control, and/orbaseline;

(b) a reduction in expired CO levels as compared to a subject who hasbeen administered an NRT, a control subject, placebo control, and/orbaseline;

(c) a reduction in the subject's serum and/or plasma cotinine levelscompared to a subject who has been administered an NRT, a controlsubject, placebo control, and/or baseline;

(d) an increase in quit rate as compared to a subject who has beenadministered an NRT, a control subject, placebo control, and/orbaseline;

(e) no change, no increase, or a decrease in adverse events compared toa subject who has been administered an NRT, a control subject, placebocontrol, and/or baseline;

(f) an increase in the subject's odds ratio as compared to a subject whohas been administered an NRT, a control subject, placebo control, and/orbaseline;

(g) an increase in abstinence compared to a subject who has beenadministered an NRT, a control subject, placebo control, and/orbaseline;

(h) a reduction in nicotine cravings and/or tobacco cravings compared toa subject who has been administered an NRT, a control subject, placebocontrol, and/or baseline;

(i) a reduction of the severity of nicotine withdrawal symptoms comparedto a subject who has been administered an NRT, a control subject,placebo control, and/or baseline;

(j) a reduction of the severity of anxiety compared to a subject who hasbeen administered an NRT, a control subject, placebo control, and/orbaseline; and/or

(k) a reduction of the severity of depression compared to a subject whohas been administered an NRT, a control subject, placebo control, and/orbaseline.

In one embodiment, methods of the present disclosure comprise measuringbaseline levels of one or more markers set forth in (a)-(k) above priorto dosing the subject or subject group. In another embodiment, themethods comprise administering a composition as disclosed herein to thesubject after baseline levels of one or more markers set forth in(a)-(k) are determined, and subsequently taking an additionalmeasurement of said one or more markers. In another embodiment, upontreatment with a composition of the present disclosure, the subjectexhibits one or more of:

(a) a reduction in units of nicotine used per day, such as cigarettessmoked per day or vaping per day by at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 50%, ormore, compared to a subject who has been administered an NRT, a controlsubject, placebo control, and/or baseline;

(b) a reduction in expired CO levels of about 5% to about 100% comparedto baseline, control, or placebo levels, for example about 5%, about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, or more, compared to a subject who has beenadministered an NRT, a control subject, placebo control, and/orbaseline;

(c) a reduction in serum and/or plasma cotinine levels of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, or more, as compared to asubject who has been administered an NRT, a control subject, placebocontrol, and/or baseline;

(d) an increase in quit rate of about 5% to about 100%, about 5% toabout 75%, about 5% to about 50%, about 25% to about 75%, about 25% toabout 50%, about 30% to about 50%, about 30% to about 75%, about 30% toabout <100%, or about 30% to about 100%, as compared to a subject whohas been administered an NRT, a control subject, placebo control, and/orbaseline;

(e) no change, no increase, or a decrease in adverse events of about 0%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, or more compared to a subject whohas been administered an NRT, a control subject, placebo control, and/orbaseline;

(f) an increase in the subject's odds ratio of about 0%, about 5%, about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, or more, compared to a subject who has beenadministered an NRT, a control subject, placebo control, and/orbaseline;

(g) an increase in abstinence of about 0%, about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, or more compared to a subject who has been administered anNRT, a control subject, placebo control, and/or baseline;

(h) a reduction in tobacco cravings of about 0%, about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, or more, compared to a subject who has been administeredan NRT, a control subject, placebo control, and/or baseline;

(i) a reduction of the severity of nicotine withdrawal symptoms of about0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, or more, compared to asubject who has been administered an NRT, a control subject, placebocontrol, and/or baseline;

(j) a reduction of the severity of anxiety of about 0%, about 5%, about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, or more compared to a subject who has beenadministered an NRT, a control subject, placebo control, and/orbaseline; and/or

(k) a reduction of the severity of depression of about 0%, about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, or more, compared to a subject who has beenadministered an NRT, a control subject, placebo control, and/orbaseline.

In some embodiments, methods of the present disclosure include treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, the method comprising administeringcytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine three times daily to the subject. In certain embodiments, thesubject experiences no adverse events after receiving the cytisinetreatment. In some embodiments, the adverse event is selected from thegroup consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation. In certain embodiments, the subjectexperiences no nausea after receiving the cytisine treatment. In someembodiments, cytisine is administered for about 6 weeks or for about 12weeks. In some embodiments, the unit dose of cytisine comprises (a) twotablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine, (b)a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or (c)three tablets, each tablet containing 1.0 mg of cytisine. In someembodiments, the subject is a refractory patient who has failedtreatment with one or more nicotine addiction, nicotine dependence, orsmoking cessation treatments. In some embodiments, the nicotineaddiction, nicotine dependence, or smoking cessation treatments areselected from NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, and a combination thereof.In some embodiments, the subject (a) smoked ten or more cigarettes orused ten or more vapes per day prior to the administration of cytisine,(b) has expired air CO concentration of about 10 ppm or greater prior tothe administration of cytisine, or (c) a combination of (a) and (b). Insome embodiments, the methods further comprise providing behavioralsupport to the subject.

In some embodiments, methods of the present disclosure include treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, the method comprising administeringcytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine three times daily to the subject wherein the subjectexperiences no adverse events after receiving the cytisine treatment. Insome embodiments, the adverse event is selected from the groupconsisting of an URTI, abnormal dreams, nausea, insomnia, headache,fatigue, and constipation.

In some embodiments, methods of the present disclosure include treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, the method comprising administeringcytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine three times daily to the subject wherein the subjectexperiences no nausea after receiving the cytisine treatment.

In some embodiments, methods of the present disclosure include treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, the method comprising administeringcytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine three times daily to the subject for about 6 weeks or for about12 weeks. In some embodiments, the unit dose of cytisine comprises (a)two tablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine,(b) a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or(c) three tablets, each tablet containing 1.0 mg of cytisine.

In some embodiments, methods of the present disclosure include treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, the method comprising administeringcytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine three times daily to the subject wherein the subject is arefractory patient who has failed treatment with one or more nicotineaddiction, nicotine dependence, or smoking cessation treatments. In someembodiments, the nicotine addiction, nicotine dependence, or smokingcessation treatments are selected from NRT, administration of bupropion,administration of varenicline, electronic cigarettes, vaping, and acombination thereof.

In some embodiments, methods of the present disclosure include treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, the method comprising administeringcytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine three times daily to the subject wherein the subject (a) smokedten or more cigarettes per day prior to the administration of cytisine,(b) has expired air CO concentration of about 10 ppm or greater prior tothe administration of cytisine, or (c) a combination of (a) and (b).

In some embodiments, methods of the present disclosure include treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, the method comprising administeringcytisine provided in a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine three times daily to the subject, and providing behavioralsupport to the subject.

Methods of the present disclosure further include treatment of nicotineaddiction or nicotine dependence in a subject in need thereof, themethod comprising administering cytisine to the subject, wherein thesubject is a refractory patient who has failed treatment with one ormore nicotine addiction or nicotine dependence treatments. In certainembodiments, the nicotine addiction or nicotine dependence treatmentscomprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof. Insome embodiments, cytisine is provided in a unit dose of about 1.0 mg toabout 6.0 mg of cytisine three to six times daily to a subject in needthereof. In certain embodiments, cytisine is provided in a unit dose of3.0 mg of cytisine three times daily to a subject in need thereof. Insome embodiments, the unit dose of cytisine comprises (a) two tablets,each tablet either containing 1.5 mg or 3.0 mg of cytisine, (b) a singletablet either containing 1.5 mg or 3.0 mg of cytisine, or (c) threetablets, each tablet containing 1.0 mg of cytisine. In some embodiments,cytisine is administered for about 6 weeks or for about 12 weeks. Insome embodiments, the subject experiences no adverse events afterreceiving the cytisine treatment. In certain embodiments, the adverseevent is selected from the group consisting of an URTI, abnormal dreams,nausea, insomnia, headache, fatigue, and constipation. In someembodiments, the subject (a) smoked ten or more cigarettes per day priorto the administration of cytisine, (b) has expired air CO concentrationof about 10 ppm or greater prior to the administration of cytisine, or(c) a combination of (a) and (b).

Methods of the present disclosure further provide methods of preventingsmoking and/or vaping relapse in a subject in need thereof, the methodcomprising administering cytisine provided in a unit dose of (a) twotablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine, (b)a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or (c)three tablets, each tablet containing 1.0 mg of cytisine, three timesdaily to the subject. In some embodiments, cytisine is administered forabout 6 weeks or for about 12 weeks. In some embodiments, the subjectexperiences no adverse events after receiving the cytisine treatment. Incertain embodiments, the adverse event is selected from the groupconsisting of an URTI, abnormal dreams, nausea, insomnia, headache,fatigue, and constipation. In some embodiments, the subject (a) smokedten or more cigarettes per day prior to the administration of cytisine,(b) has expired air CO concentration of about 10 ppm or greater prior tothe administration of cytisine, or (c) a combination of (a) and (b). Insome embodiments, the subject is a refractory patient who has failedtreatment with one or more smoking cessation treatments. In certainembodiments, the smoking cessation treatments comprise NRT,administration of bupropion, administration of varenicline, electroniccigarettes, vaping, or a combination thereof.

Methods of the present disclosure further include preventing smokingand/or vaping relapse in a subject in need thereof, the methodcomprising administering cytisine to the subject, wherein the subject isa refractory patient who has failed treatment with one or more smokingcessation treatments selected from the group consisting of NRT,administration of bupropion, administration of varenicline, electroniccigarettes, vaping, or a combination thereof. In some embodiments, thesubject (a) smoked ten or more cigarettes per day prior to theadministration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b). In some embodiments, the unit dose ofcytisine comprises (a) two tablets, each tablet either containing 1.5 mgor 3.0 mg of cytisine, (b) a single tablet either containing 1.5 mg or3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mgof cytisine, three times daily to the subject, and wherein cytisine isadministered for about 6 weeks or for about 12 weeks. In someembodiments, the subject experiences no adverse events selected from thegroup consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation after receiving the cytisinetreatment.

The present disclosure also provides medicaments, such as, a medicamentcomprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine fortreating a nicotine addiction, a nicotine dependence, promotingcessation of smoking and/or vaping, and/or promoting a reduction insmoking and/or vaping in a subject in need thereof, wherein themedicament is for three times daily oral administration to the subject.In some embodiments, the subject experiences no adverse events afterreceiving the cytisine treatment. In certain embodiments, the adverseevent is selected from the group consisting of an URTI, abnormal dreams,nausea, insomnia, headache, fatigue, and constipation. In certainembodiments, the subject experiences no nausea after receiving thecytisine treatment. In some embodiments, cytisine is administered forabout 6 weeks or for about 12 weeks. In some embodiments, the unit doseof cytisine comprises (a) two tablets, each tablet either containing 1.5mg or 3.0 mg of cytisine, (b) a single tablet either containing 1.5 mgor 3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0mg of cytisine. In some embodiments, the subject is a refractory patientwho has failed treatment with one or more nicotine addiction, nicotinedependence, or smoking cessation treatments. In certain embodiments, thenicotine addiction, nicotine dependence, or smoking cessation treatmentsare selected from NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, and a combination thereof.In some embodiments, the subject (a) smoked ten or more cigarettes perday prior to the administration of cytisine, (b) has expired air COconcentration of about 10 ppm or greater prior to the administration ofcytisine, or (c) a combination of (a) and (b). In some embodiments, themethods further comprise providing behavioral support to the subject.

The present disclosure also provides medicaments, such as, a medicamentcomprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine fortreating a nicotine addiction, a nicotine dependence, promotingcessation of smoking and/or vaping, and/or promoting a reduction insmoking and/or vaping in a subject in need thereof, wherein themedicament is for three times daily oral administration to the subject,and wherein the subject experiences no adverse events after receivingthe cytisine treatment. In certain embodiments, the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation. In certain embodiments,the subject experiences no nausea after receiving the cytisinetreatment.

The present disclosure further provides medicaments, such as, amedicament comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine for treating a nicotine addiction, a nicotine dependence,promoting cessation of smoking and/or vaping, and/or promoting areduction in smoking and/or vaping in a subject in need thereof, andwherein the cytisine is administered for about 6 weeks or for about 12weeks. In some embodiments, the unit dose of cytisine comprises (a) twotablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine, (b)a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or (c)three tablets, each tablet containing 1.0 mg of cytisine.

In some embodiments, the present disclosure further provides amedicament comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine for treating a nicotine addiction, a nicotine dependence,promoting cessation of smoking and/or vaping, and/or promoting areduction in smoking and/or vaping in a subject in need thereof, andwherein the subject is a refractory patient who has failed treatmentwith one or more nicotine addiction or smoking cessation treatments. Incertain embodiments, the nicotine addiction or smoking cessationtreatments are selected from NRT, administration of bupropion,administration of varenicline, electronic cigarettes, vaping, and acombination thereof.

In some embodiments, the present disclosure further provides amedicament comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine for treating a nicotine addiction, a nicotine dependence,promoting cessation of smoking and/or vaping, and/or promoting areduction in smoking and/or vaping in a subject in need thereof, andwherein the subject (a) smoked ten or more cigarettes per day prior tothe administration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b).

The present disclosure further provides medicaments, such as, amedicament comprising cytisine for treating a nicotine addiction or anicotine dependence in a subject that is a refractory patient who hasfailed treatment with one or more nicotine addiction or nicotinedependence treatments, wherein the medicament is for three times dailyoral administration to the subject. In some embodiments, the nicotineaddiction or nicotine dependence treatments comprise NRT, administrationof bupropion, administration of varenicline, electronic cigarettes,vaping, or a combination thereof. In some embodiments, cytisine isprovided in a unit dose of about 1.0 mg to about 6.0 mg of cytisinethree to six times daily to a subject in need thereof. In certainembodiments, cytisine is provided in a unit dose of 3.0 mg of cytisinethree times daily to a subject in need thereof. In some embodiments, theunit dose of cytisine comprises (a) two tablets, each tablet eithercontaining 1.5 mg or 3.0 mg of cytisine, (b) a single tablet eithercontaining 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, eachtablet containing 1.0 mg of cytisine. In some embodiments, cytisine isadministered for about 6 weeks or for about 12 weeks. In someembodiments, the subject experiences no adverse events after receivingthe cytisine treatment. In certain embodiments, the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation. In some embodiments, thesubject (a) smoked ten or more cigarettes per day prior to theadministration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b).

In some embodiments, the medicament comprises a unit dose of cytisine in(a) two tablets, each tablet either containing 1.5 mg or 3.0 mg ofcytisine, (b) a single tablet either containing 1.5 mg or 3.0 mg ofcytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine for preventing smoking and/or vaping relapse in a subject inneed thereof, wherein the medicament is for three times daily oraladministration to the subject. In certain embodiments, cytisine isadministered for about 6 weeks or for about 12 weeks. In someembodiments, the subject experiences no adverse events after receivingthe cytisine treatment. In certain embodiments, the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation. In some embodiments, thesubject (a) smoked ten or more cigarettes per day prior to theadministration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b). In some embodiments, the subject is arefractory patient who has failed treatment with one or more smokingcessation treatments. In certain embodiments, the smoking cessationtreatments comprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

The present disclosure further provides medicaments, such as, amedicament comprising cytisine for preventing smoking and/or vapingrelapse in a subject that is a refractory patient who has failedtreatment with one or more nicotine addiction or nicotine dependencetreatments selected from the group consisting of NRT, administration ofbupropion, administration of varenicline, electronic cigarettes, orvaping, wherein the medicament is for three times daily oraladministration to the subject. In some embodiments, the subject (a)smoked ten or more cigarettes per day prior to the administration ofcytisine, (b) has expired air CO concentration of about 10 ppm orgreater prior to the administration of cytisine, or (c) a combination of(a) and (b). In some embodiments, the unit dose of cytisine comprises(a) two tablets, each tablet either containing 1.5 mg or 3.0 mg ofcytisine, (b) a single tablet either containing 1.5 mg or 3.0 mg ofcytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine, and wherein cytisine is administered for about 6 weeks or forabout 12 weeks. In some embodiments, the subject experiences no adverseevents selected from the group consisting of an URTI, abnormal dreams,nausea, insomnia, headache, fatigue, and constipation after receivingthe cytisine treatment.

In some embodiments, the present disclosure provides uses of a unit doseof 3.0 mg, 1.5 mg, or 1.0 mg of cytisine for treating a nicotineaddiction, a nicotine dependence, promoting cessation of smoking and/orvaping, and/or promoting a reduction in smoking and/or vaping in asubject in need thereof, wherein the cytisine is for three times dailyoral administration to the subject. In some embodiments, the subjectexperiences no adverse events after receiving the cytisine treatment. Incertain embodiments, the adverse event is selected from the groupconsisting of an URTI, abnormal dreams, nausea, insomnia, headache,fatigue, and constipation. In certain embodiments, the subjectexperiences no nausea after receiving the cytisine treatment. In someembodiments, cytisine is administered for about 6 weeks or for about 12weeks. In some embodiments, the unit dose of cytisine comprises (a) twotablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine, (b)a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or (c)three tablets, each tablet containing 1.0 mg of cytisine. In someembodiments, the subject is a refractory patient who has failedtreatment with one or more nicotine addiction, nicotine dependence, orsmoking cessation treatments. In certain embodiments, the nicotineaddiction, nicotine dependence, or smoking cessation treatments areselected from NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, and a combination thereof.In some embodiments, the subject (a) smoked ten or more cigarettes perday prior to the administration of cytisine, (b) has expired air COconcentration of about 10 ppm or greater prior to the administration ofcytisine, or (c) a combination of (a) and (b). In some embodiments, theuses further include providing behavioral support to the subject.

The present disclosure further provides uses of cytisine, such as fortreating a nicotine addiction or nicotine dependence in a subject thatis a refractory patient who has failed treatment with one or morenicotine addiction or nicotine dependence treatments, wherein thecytisine is for three times daily oral administration to the subject. Incertain embodiments, the nicotine addiction or nicotine dependencetreatments comprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof. Insome embodiments, cytisine is provided in a unit dose of about 1.0 mg toabout 6.0 mg of cytisine three to six times daily to a subject in needthereof. In certain embodiments, cytisine is provided in a unit dose of3.0 mg of cytisine three times daily to a subject in need thereof. Incertain embodiments, the unit dose of cytisine comprises (a) twotablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine, (b)a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or (c)three tablets, each tablet containing 1.0 mg of cytisine. In someembodiments, cytisine is administered for about 6 weeks or for about 12weeks. In some embodiments, the subject experiences no adverse eventsafter receiving the cytisine treatment. In certain embodiments, theadverse event is selected from the group consisting of an URTI, abnormaldreams, nausea, insomnia, headache, fatigue, and constipation. In someembodiments, the subject (a) smoked ten or more cigarettes per day priorto the administration of cytisine, (b) has expired air CO concentrationof about 10 ppm or greater prior to the administration of cytisine, or(c) a combination of (a) and (b).

In some embodiments, uses of a unit dose of cytisine in the form of (a)two tablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine,(b) a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or(c) three tablets, each tablet containing 1.0 mg of cytisine includepreventing smoking relapse in a subject in need thereof, wherein thecytisine is for three times daily oral administration to the subject. Insome embodiments, cytisine is administered for about 6 weeks or forabout 12 weeks. In some embodiments, the subject experiences no adverseevents after receiving the cytisine treatment. In certain embodiments,the adverse event is selected from the group consisting of an URTI,abnormal dreams, nausea, insomnia, headache, fatigue, and constipation.In some embodiments, the subject (a) smoked ten or more cigarettes perday prior to the administration of cytisine, (b) has expired air COconcentration of about 10 ppm or greater prior to the administration ofcytisine, or (c) a combination of (a) and (b). In some embodiments, thesubject is a refractory patient who has failed treatment with one ormore smoking cessation treatments. In certain embodiments, the smokingcessation treatments comprise NRT, administration of bupropion,administration of varenicline, electronic cigarettes, vaping, or acombination thereof.

In some embodiments, uses of cytisine for preventing smoking relapse ina subject that is a refractory patient who has failed treatment with oneor more nicotine addiction or nicotine dependence treatments selectedfrom the group consisting of NRT, administration of bupropion,administration of varenicline, electronic cigarettes, or vaping, whereinthe cytisine is for three times daily oral administration to thesubject. In some embodiments, the subject (a) smoked ten or morecigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b). Incertain embodiments, the unit dose of cytisine comprises (a) twotablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine, (b)a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or (c)three tablets, each tablet containing 1.0 mg of cytisine, and whereincytisine is administered for about 6 weeks or for about 12 weeks. Insome embodiments, the subject experiences no adverse events selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation after receiving the cytisinetreatment.

The present disclosure further provides uses of tablets comprising about1.0 mg or 1.5 mg of cytisine are for three times daily oraladministration of about 3.0 mg of cytisine to a subject to treat anicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in the subject. In some embodiments, the subject experiences noadverse events after receiving the cytisine treatment. In certainembodiments, the adverse event is selected from the group consisting ofan URTI, abnormal dreams, nausea, insomnia, headache, fatigue, andconstipation. In certain embodiments, the subject experiences no nauseaafter receiving the cytisine treatment. In some embodiments, cytisine isadministered for about 6 weeks or for about 12 weeks. In someembodiments, a unit dose of cytisine comprises (a) two tablets, eachtablet either containing 1.5 mg or 3.0 mg of cytisine, (b) a singletablet either containing 1.5 mg or 3.0 mg of cytisine, or (c) threetablets, each tablet containing 1.0 mg of cytisine. In some embodiments,the subject is a refractory patient who has failed treatment with one ormore nicotine addiction, nicotine dependence, or smoking cessationtreatments. In certain embodiments, the nicotine addiction, nicotinedependence, or smoking cessation treatments are selected from NRT,administration of bupropion, administration of varenicline, electroniccigarettes, vaping, and a combination thereof. In some embodiments, thesubject (a) smoked ten or more cigarettes per day prior to theadministration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b). In some embodiments, the uses furthercomprise providing behavioral support to the subject.

In some embodiments, the uses of tablets comprising about 1.0 mg or 1.5mg of cytisine are for three times daily oral administration of about3.0 mg of cytisine to a subject that is a refractory patient who hasfailed treatment with one or more nicotine addiction or nicotinedependence treatments to treat a nicotine addiction or nicotinedependence in the subject. In certain embodiments, the nicotineaddiction or nicotine dependence treatments comprise NRT, administrationof bupropion, administration of varenicline, electronic cigarettes,vaping, or a combination thereof. In some embodiments, cytisine isprovided in a unit dose of about 1.0 mg to about 6.0 mg of cytisinethree to six times daily to a subject in need thereof. In certainembodiments, cytisine is provided in a unit dose of 3.0 mg of cytisinethree times daily to a subject in need thereof. In some embodiments, theunit dose of cytisine comprises (a) two tablets, each tablet eithercontaining 1.5 mg or 3.0 mg of cytisine, (b) a single tablet eithercontaining 1.5 mg or 3.0 mg of cytisine, or (c) three tablets, eachtablet containing 1.0 mg of cytisine. In some embodiments, cytisine isadministered for about 6 weeks or for about 12 weeks. In someembodiments, the subject experiences no adverse events after receivingthe cytisine treatment. In certain embodiments, the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation. In some embodiments, thesubject (a) smoked ten or more cigarettes per day prior to theadministration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b).

In some embodiments, the uses of tablets comprising about 1.0 mg orabout 1.5 mg of cytisine are for three times daily oral administrationof about 3.0 mg of cytisine to a subject to prevent smoking and/orvaping relapse in the subject. In certain embodiments, the cytisine isadministered for about 6 weeks or for about 12 weeks. In someembodiments, the subject experiences no adverse events after receivingthe cytisine treatment. In certain embodiments, the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation. In some embodiments, thesubject (a) smoked ten or more cigarettes per day prior to theadministration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b). In some embodiments, the subject is arefractory patient who has failed treatment with one or more smokingcessation treatments. In certain embodiments, the smoking cessationtreatments comprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

In some embodiments, the uses of tablets comprising about 1.0 mg orabout 1.5 mg of cytisine are for three times daily oral administrationof about 3.0 mg of cytisine to a subject who has failed treatment withone or more nicotine addiction or nicotine dependence treatmentsselected from the group consisting of NRT, administration of bupropion,administration of varenicline, electronic cigarettes, or vaping toprevent smoking relapse in the subject. In some embodiments, the subject(a) smoked ten or more cigarettes per day prior to the administration ofcytisine, (b) has expired air CO concentration of about 10 ppm orgreater prior to the administration of cytisine, or (c) a combination of(a) and (b). In some embodiments, a unit dose of cytisine comprises (a)two tablets, each tablet either containing 1.5 mg or 3.0 mg of cytisine,(b) a single tablet either containing 1.5 mg or 3.0 mg of cytisine, or(c) three tablets, each tablet containing 1.0 mg of cytisine, andwherein cytisine is administered for about 6 weeks or for about 12weeks. In some embodiments, the subject experiences no adverse eventsselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation after receiving thecytisine treatment.

Thus, in yet another aspect, provided herein is a method of treating ofnicotine addiction or nicotine dependence in a subject, comprisingadministering cytisine to a subject in need thereof, wherein the subjectis a refractory patient who has failed treatment with one or morenicotine addiction or nicotine dependence treatments. Suitable unitdoses include doses between about 1.0 mg and about 6 mg which can beadministered three to six times daily, for example, at about equalintervals. For example, in some embodiments, the methods compriseadministering cytisine provided in a unit dose of 3.0 mg of cytisinethree times daily to a refractory patient. Any suitable duration ofadministration can be used in the methods disclosed herein, for example,about 26 weeks, about 12 weeks, or about 6 weeks. In some embodiments,the treatment is administered for about 6 weeks.

In some embodiments, the methods disclosed herein can further compriseproviding behavioral support to the subject, for example, a refractorypatient. Behavioral support can include counseling which can furtherinclude, but is not limited to, the following topics: abstinence, pastquit experience, anticipate triggers or challenges in the upcomingattempt, alcohol use, proximity to and frequency around other nicotineusers (e.g., smokers, vapers), recognition of dangerous situations, anddevelopment of coping skills.

In some embodiments, the methods disclosed herein can further compriseproviding one or more questionnaires to the subject. Non-limitingexamples of the one or more questionnaires include an E-cigaretteDependence Scale questionnaire, a marijuana craving questionnaire-shortform, the Fagerström Test for Nicotine Dependence, the SmokingSelf-Efficacy questionnaire (SEQ-12), the Brief Questionnaire of SmokingUrges (QSU-Brief) questionnaire, the Minnesota Nicotine Withdrawal Scale(MNWS) questionnaire, the “Since Last Visit” C-SSRS questionnaire, andthe HADS questionnaire. In certain embodiments, the questionnaire(s) canbe provided to the subject at any time during administration of thecomposition, before administration of the composition, or afteradministration of the composition. In some embodiments, the one or morequestionnaires are provided to the subject once, twice, three times,four times, five times, six times, seven times, eight times, nine times,ten times, 15 times, 20 times, or 30 times.

The referenced patents, patent applications, and scientific literaturereferred to herein are hereby incorporated by reference in theirentirety as if each individual publication, patent, or patentapplication were specifically and individually indicated to beincorporated by reference. Any conflict between any reference citedherein and the specific teachings of this specification shall beresolved in favor of the latter. Likewise, any conflict between anart-understood definition of a word or phrase and a definition of theword or phrase as specifically taught in this specification shall beresolved in favor of the latter.

As can be appreciated from the disclosure above, the present inventionhas a wide variety of applications. The invention is further illustratedby the following examples, which are only illustrative and are notintended to limit the definition and scope of the invention in any way.

Example 1: Impact of Cytisine on Treating Nicotine Addiction

This was a six-arm, multi-center, double-blind, randomized,placebo-controlled study conducted in male or female adults years ofage, smoking 10+ cigarettes daily, and willing to set a quit date thatis 5-7 days after randomization. This study was designed to evaluate theeffectiveness of 1.5 mg of cytisine versus placebo using the commercialtitration schedule approved in Central and Eastern Europe. The studyalso evaluated the effectiveness of a simplified TID dosing schedule for1.5 mg and an increased dose of 3.0 mg (using both the commercialtitration (COM) and simplified TID dosing schedules). The overall goalof the study was to obtain estimates of effect size for efficacy andsafety endpoints that will be used to inform the design of future Phase3 studies.

The dosing schedules for the study are shown in FIG. 1. The study wasdouble-blinded to dose but not to the administration schedule, and thestudy arms were as shown in FIG. 2. Study treatment started the dayafter randomization such that study treatment was initiated prior to thequit date, as shown in FIG. 3.

The primary efficacy endpoint for this study was the percent reductionin the number of cigarettes smoked during treatment, which wascalculated as follows:

$100 - {\left\lbrack {\frac{N}{B \times D} \times 100} \right\rbrack \%}$

where N=total number of cigarettes smoked, B=number of cigarettes smokedat baseline and D=number of days.

The secondary efficacy endpoint was the quit rate (confirmed by CO<10ppm) and included an analysis at week 4 (i.e., the end of treatment) andsustained (4-week) abstinence from Week 5 to Week 8 (i.e., offtreatment).

The subject demographics are summarized in FIG. 4. The cigarettessubject's smoked before and after treatment are shown in FIG. 5.

1.1 Results

Table 1 summarizes the demographics of the subjects. In total, 254 maleor female adults ≥18 years of age who smoked ≥10 cigarettes daily andwere willing to set a quit date 5 to 7 days after randomization wereenrolled in the study. Demographics and baseline characteristics weregenerally well balanced across both schedules and treatment arms.

TABLE 1 Subject Demographics Downward Titration TID 1.5 mg 3.0 mg 1.5 mg3.0 mg Placebo ALL (n = 51) (n = 50) (n = 52) (n = 50) (n = 51) (n =254) Sex Male 23 (45%) 30 (60%) 23 (44%) 25 (50%) 20 (39%) 121 (47%)Female 28 (55%) 20 (40%) 29 (56%) 25 (50%) 31(61%) 133 (53%) Race White43 (84%) 40 (80%) 37 (71%) 41(82%) 39 (76%) 200 (80%) Black 7 (14%) 9(18%) 13 (25%) 7 (14%) 10 (20%) 46 (18%) Asian 0 0 1 (2%) 1 (2%) 1 (2%)3 (1%) Pacific 0 0 0 0 0 0 Native 0 1 (2%) 1 (2%) 0 0 3 (1%) Other 1(2%) 0 0 1 (2%) 1 (2%) 3 (1%) Age (mean years) 49.8 50.0 47.0 46.3 48.948.4 Weight (mean kg) 82.1 83.0 80.7 79.5 80.2 81.1 BMI (mean kg/m²)27.6 27.8 27.9 27.1 27.9 27.7

Of the study population, 53% percent were female and 47% male. 79% ofthe study population was white, with 18% black and 3% of another race.Smoking diary compliance, on which the primary analysis was based inpart, was high for all treatment arms. Study drug compliance was >94%for all treatment arms with slightly higher compliance with the TIDschedule (>98%). The mean treatment duration was 23.4 days and 96.6% ofthe subjects received the mean doses of cytisine.

Table 2 summarizes the smoking history of the subjects in all treatmentarms. Overall, the study population represented highly addictive smokerswho on average were 48.4 years old and had been smoking for 32 years,meaning that most of them had started smoking in their adolescent years.In addition, they had an average of 4.5 prior quit attempts with thelast quit attempt approximately 3.7 years prior to entering the studyand were currently smoking on average a pack of cigarettes a day. Of theprevious quit attempts, 35% of the subjects had previously receivedvarenicline, 16% of the subject had bupropion, and 48% of the subjectsan NRT.

TABLE 2 Subject Smoking History Downward Titration TID 1.5 mg 3.0 mg 1.5mg 3.0 mg Placebo ALL (n = 51) (n = 50) (n = 52) (n = 50) (n = 51) (n =254) Smoking duration 33.3 33.2 30.9 30.0 33.0 32.1 (mean years) Dailysmoking 20 20 20 18 20 20 (median cigarettes) Prev quit attempts 5.4 3.84.7 3.8 4.9 4.5 (mean) Previous treatments Chantix ® 21 (41%) 13 (26%)21(40%) 18 (36%) 19 (37%) 92 (36%) Zyban ® 9 (18%) 3 (6%) 9 (17%) 7(14%) 12 (24%) 40 (16%) NRT gum 20 (39%) 12 (24%) 20 (38%) 16 (32%) 24(47%) 92 (36%) NRT patch 23 (45%) 19 (38%) 27 (52%) 25 (50%) 28 (55%)122 (48%) e-cigarettes/vaping 15 (29%) 11(22%) 19 (36%) 13 (26%) 18(35%) 76 (30%)Analyses from the international EAGLES trial provided clear evidencethat smoking at a young age and being of U.S. origin was associated withlower success rates for quitting. The lower success rate in U.S. smokerssupports the view that smokers in the U.S. may have reached a point inthe tobacco epidemic such that those who continue to smoke, despitestrong cultural pressures not to, have particular characteristics thatmake it more difficult for them to stop smoking.

Overall, study drug compliance was high for all treatment arms with theTID schedule better (98.18%) than the commercial schedule (94.90%). Morespecifically, Table 3 summarizes the study drug compliance in alltreatment arms. Study drug compliance ranged from 96.7% to 99.5% in theTID arms while study drug compliance ranged from 94.2% to 96.4% in theCOM arms.

TABLE 3 Study Drug Compliance Downward Titration Schedule TID Schedule1.5 mg 3.0 mg Placebo 1.5 mg 3.0 mg Placebo N = 51 N = 50 N = 25 N = 52N = 52 N = 26 Treatment Duration 23.8 (4.76) 23.5 (4.49) 23.9 (4.06)25.0 (0.14) 24.9 (0.72) 24.3 (3.53) Mean Days (std) Percent of Doses 5.1(18.1) 5.8 (15.8) 3.6 (13.7) 0.5 (1.2) 2.4 (7.7) 3.3 (13.6) Missed Mean% (std) Compliance* 94.9% 94.2% 96.4% 99.5% 97.6% 96.7% 100% 33 (64.7%)32 (64.0%) 20 (88.0%) 42 (80.8%) 37 (74.0%) 20 (76.9%)  90%-<100% 13(25.5%) 12 (24.0%) 3 (12.0%) 10 (19.2%) 10 (20.0%) 5 (19.2%)  80%-<90% 3(5.9%) 1 (2.0%) 3 (5.9%) 0 1 (2.0%) 1 (3.8%) <80% 2 (3.9%) 5 (10.0%) 2(3.9%) 0 2 (4.0%) *Defined as [(# doses prescribed − # missed doses)/#doses prescribed] × 100.

The reduction in cigarettes smoked in all treatment arms is shown inFIG. 6 and summarized in Table 4. Results from the primary analysesdemonstrated a significant reduction in percentage of expectedcigarettes smoked (Cigarette Score) in both COM arms. When pooling theplacebo arms, the Cigarette Score was significantly reduced in both COMarms, the 1.5 mg TID arm, and approached significance in the 3.0 mg TIDarm. Subjects treated with 1.5 mg or 3.0 mg of cytisine using the COMschedule smoked approximately 14% to 16% fewer cigarettes than expectedversus placebo. Subjects treated with 1.5 mg or 3.0 mg of cytisine onthe TID schedule smoked approximately 9% to 12% fewer cigarettes thanexpected versus the placebo arm.

TABLE 4 Reduction of Cigarettes Smoked and CO Reduction in Reductioncigarettes smoked p-value in CO Titration 1.5 80% 0.001 78% 3.0 78%0.003 71% Placebo 62% 40% TID 1.5 79% 0.009 71% 3.0 74% 0.052 80%Placebo 62% 29%

Although the decreases on the TID schedule were not as high as thoseseen on the COM schedule, it should be noted that subjects in theplacebo arm on the TID schedule reported a higher reduction incigarettes smoked than subjects in the placebo arm on the COM schedule.The TID placebo subjects smoked only one-third as many cigarettes asthey normally would (LS mean: 35.30%) versus the COM placebo subjects atone-half as many cigarettes smoked (LS mean: 47.10%), which possiblymasked the cytisine treatment effect on the TID schedule.

Expired CO levels were also measured during this study as an objectivebiochemical marker for reduction in smoking. The reduction in CO in alltreatment arms is shown in FIG. 6 and summarized in Table 4. In allcytisine-treated arms, the reduction in CO (55% to 62% reduction) wasconsistent with the reported reduction in cigarettes smoked (e.g., arange of 25% to 32% as Cigarette Scores represents a 75% to 68%reduction in cigarettes smoking). Conversely, in the placebo-treatedarms, the reported reductions in the number of cigarettes smoked (e.g.,41% as the Cigarette Score, representing a 59% reduction in cigarettessmoked) was not paralleled by a corresponding reduction in CO at only29%. A similar pattern for plasma cotinine levels was observed with fargreater reductions in cotinine levels in the cytisine arms compared toplacebo arms.

The changes in these objective markers suggest that, in general,placebo-treated subjects over-reported their reduction in cigarettessmoked. It also suggests that the real differences in Cigarette Scoresbetween subjects treated with cytisine and those treated with placebowere greater than those actually observed.

The quit rates for arms of the TID schedule versus placebo is shown inFIGS. 7 and 8 and summarized in Table 5. Results for the initial quitrate at Week 4 demonstrated both arms of the TID schedule had high oddsof success of quitting smoking compared with placebo; subjects in the3.0 mg of cytisine arm had the best odds of success for quittingsmoking: OR: 6.31 (95% CI: 2.28, 18.45). The OR for the 1.5 mg ofcytisine arm on the TID schedule was 5.81 (95% CI: 2.12, 16.87). On theCOM schedule, the ORs for the 1.5 and 3.0 mg of cytisine arms were 5.59(95% CI: 2.03, 16.29) and 5.38 (95% CI: 1.95, 15.72), respectively.

TABLE 5 Quit Rates-Cytisinicline versus Placebo End-of-TreatmentContinuous Abstinence Week 4 Weeks 5 to 8 Quit Rate p-value Quit Ratep-value Titration 1.5 51% <0.001 22% 0.09 3.0 50% <0.001 16% 0.23Placebo 16%  8% TID 1.5 52% <0.001 27% 0.018 3.0 54% <0.001 30% 0.005Placebo 15%  8%

Referring to FIGS. 7 and 8 and Table 5, for the prolonged abstinencefrom Week 5 to Week 8 endpoint, both arms of the TID schedule had higherodds of success for abstinence compared with placebo; subjects in the3.0 mg of cytisine arm had the best odds of success for abstinence fromWeeks 5 to 8, with an OR of 5.04 (95% CI: 1.42, 22.32). The OR for the1.5 mg of cytisine arm on the TID schedule was 4.33 (95% CI: 1.21,19.30). On the COM schedule, the ORs for the 1.5 mg of cytisine and 3.0mg arms were 3.23 (95% CI: 0.86, 14.85) and 2.24 (95% CI: 0.55, 10.82),respectively.

Table 6 summarizes a comparison of the reduction in expired CO levelsand quit rates at Week 4 and Weeks 5 to 8 for the 3.0 mg of cytisine armversus placebo.

TABLE 6 Reduction in CO and Quit Rates for 3 mg TID versus Placebo 3.0mg CYT Placebo Characteristic (N = 50) (N = 51) P Value Reduction in 80%38% p = 0.003 expired CO Week 4 54% 16% p < 0.001 Abstinence ContinuousAbstinence 30%  8% p = 0.005 (Weeks 5-8)

Subjects in the cytisine arms on the TID schedule also had higher oddsof smoking abstinence at the Weeks 6, 7, and 8 timepoints compared withsubjects in the corresponding arms on the COM schedule versus placebo,as demonstrated by higher ORs at each timepoint.

1.2 Sensitivity Objectives and General Methods

The primary outcome (Cigarette Score) and the main secondary abstinenceoutcomes were subjected to sensitivity analyses. The main secondaryabstinence outcomes were the initial quit rate at Week 4 and continued4-week abstinence through Week 5 to Week 8, confirmed by expired CO of<10 ppm designated as Cess/W5-8/CO Success. The objective was to assessthe robustness of the findings from the trial, and to performalternative analyses that might either confirm the observed results orchallenge the conclusions of the trial.

Other outcomes related to objective biochemical assessments were alsoanalyzed. The associations between these biochemical assessments areparticularly important when used as part of the definition of smokingcessation and abstinence but are also important because of absence ofassessment subjectivity.

The focus of these sensitivity analyses in this report is on thecomparison of the 3.0 mg of cytisine TID arm to the pooled placebo (0 mgof cytisine) arm. Some analyses will show the other comparisons forcontrast.

Effect of Modification Analysis Methodology

A common method for assessing robustness, consistency, and meaning ofresults from a trial is to perform Effect Modifier Analyses (EMAs). Thegoal of an EMA is to evaluate the degree to which arm effects estimatedfor discrete values of a baseline attribute differ. For example, an EMAof sex estimates sex-specific arm effects and evaluates whether theseestimates differ. If a baseline attribute to be evaluated using EMA isnot discrete, the attribute is made discrete by specifying cutpointsbased on external criteria or by using percentiles computed from thepooled data (median, tertiles, or quartiles). For example, baseline COlevels split at below 10 ppm or not or using pooled quartile values.

An EMA fits a statistical model to the data. The EMA model hasinteraction terms for detecting the existence of arm effect differencesacross discrete factor values. Heterogeneity of effect estimates isdetected when interaction terms materially improve the fit of the modelover the model without interaction terms. The improvement of fit due tointeraction terms is measured by an interaction P value, where a small Pvalue, usually less than 0.10, indicates improvement of fit.

There are two types of interactions: qualitative and quantitative. Aquantitative interaction exists when the directions of the arm effectestimates are the same for all discrete values of the factor. Aqualitative interaction exists when the direction of effects is mixedfor values of the factor.

The results from the multiple EMAs performed in this study are displayedcompactly as forest graphs, showing for each factor value thesubset-related frequencies (distribution between arms), effect estimate,and applicable confidence interval. The EMA forest graphs provide agestalt concerning the stability of the overall effect estimate for thefactors included in the graph. Complete EMA forest graphs also show foreach factor the quantitative assessment of heterogeneity from the EMAmodel, for example, the interaction P value. Also, arm effect estimatesand confidence intervals for each value of the factors are displayed inthe forest graphs. (Such forest graphs appear subsequently.)

Justification for Pooling Control Arms

The between-arm comparisons were the pairwise comparisons of each activearm to the pooled placebo arm. The justification for comparing to thepooled placebo was based on:

-   -   The absence of evidence that the two placebo arms differed with        respect to the primary or the two secondary outcomes with P        values 0.1197, 0.9963, and 0.9996, respectively, for the        stratified between-control-arm comparisons of the Cigarette        Score, initial quit success at Week 4, and Cess/W5-8/CO success        outcomes.    -   The absence of evidence that the randomization between the        placebo arms differed with respect to any of the baseline        attributes used as factors in the subsequently presented EMAs,        including clinical site.

For the purposes of sensitivity assessment, this absence of evidence ofplacebo arm differences is regarded as justification for pooling, withthe benefit of increased statistical sensitivity.

Descriptive Graphs for Daily Reported Mean Cigarettes

Longitudinal graphs for the mean of the number of cigarettes reported inthe diaries for each study treatment day (Days 1-25 followingrandomization) are presented below. Each arm and the pooled placebo armare shown in a different color or dashed versus solid lines. FIG. 5illustrates that at each day, subjects did reduce their daily number ofcigarettes smoked in an attempt to quit by the planned quit interval(Days 5-7) with abstinence by Day 8.

1.3 Biochemical Verification Analysis

Following are two longitudinal graphs of the visit means and 95%confidence intervals of CO and cotinine, respectively, by the pooledplacebo arm and cytisine-treated arms.

CO levels (ppm) were assessed during the study at screening, baseline,end of study treatment intervention (Week 4), and weekly through Week 8(FIG. 9). The screening and baseline visits' CO means were approximatelyequal for all arms. At Week 4, significant reductions in CO levels forall subjects treated in cytisine-treated arms, regardless of schedule,were observed. During the follow-up period (with only behavioralsupport) from Week 4 through Week 8, the CO means in the pooled placeboarm were approximately constant, although somewhat lower than the meansbefore the start of study treatment intervention. The means for theactive treatment arms remained distinctly lower compared to the pooledplacebo arm for all follow-up visits, although the means showed a slightupward trend.

Serum cotinine levels were exploratory and assessed only at screening,Week 4, and Week 8. Reported results for cotinine of <10 ng/mL weretransformed to 0 ng/mL prior to statistical analysis. The cotinine graphin FIG. 10 showed the same pattern as observed for CO. All subjects incytisine-treated arms had a material reduction in cotinine levels atWeek 4 and showed a slight upward trend by Week 8.

1.4 Cigarette Score Analysis

Primary Model Stratification and Covariate Assumptions

The primary model of Cigarette Score included covariates for the BMIstratification (3 levels) and the mean number of cigarettes reported byscreening diary. The validity of the conclusions from the results of theprimary model depended on there being no interaction between each ofthese covariates and the arm variable. If one or both of theseinteractions were material in the statistical model, then the magnitudeof the estimated arm effect would be a function of BMI class and/or themean number of cigarettes reported by screening diary.

The planned statistical analyses of the primary endpoint were performedand, as part of those analyses, each of the cytisine treatment arms wascompared to the Pooled Placebo arm on the primary efficacy endpoint(Cigarette Score). These analyses were performed using analysis ofvariance models with fixed effects of treatment arm and BMI (18.5 to <25kg/m²; 25 to <30 kg/m²; 30 to <35 kg/m²) and a covariate of baselinecigarettes. The analysis used a BMI variable derived from the subjects'actual BMI and omitted one subject (104-144) because the subject's BMI(39.9 kg/m²) was greater than the upper limit of the top BMI category(30 to <35 kg/m²).

Two variations on this analysis were performed as part of thesensitivity analyses. These were:

-   -   A model that used a BMI variable derived from the subject's        actual BMI, but that included all 254 subjects in the All        Randomized Set. The BMI categories used in this analysis were        18.5 to <25 kg/m²; 25 to <30 kg/m²; 30 to <35 kg/m², and 35        kg/m².    -   A model that used the BMI stratification variable at        randomization. Subject 104-144 was included in this analysis,        within the BMI stratum reported for that subject at        randomization (30 to <35 kg/m²). Consequently, this analysis        included all 254 subjects in the All Randomized Set. The BMI        categories used in this analysis were 18.5 to <25 kg/m²; 25 to        <30 kg/m²; and 30 to <35 kg/m².

FIGS. 11A-11B show a comparison between homogeneity of each group (COM 0mg and TID 0 mg, and between TID 0 mg and TID 3.0) as a factor of thepercentage of expected cigarettes smoked (Cigarette Score).

FIG. 16 and FIG. 17 are additional assessments for BMI and baseline meannumber of cigarettes interactions specifically for the 3.0 mg TID armcompared to the pooled placebo arm.

For BMI, this assessment for the existence of an interaction with armwas evaluated as an EMA using BMI as the factor, where the size of theinteraction P would be informative of the existence of this interaction(FIG. 16). The EMA interaction P value for BMI was 0.1303, not smallenough to induce concern, but based on the stratum-specific effect sizeestimates there was a suggestion of possibly more efficacy for high BMIpatients as compared to lower BMI subjects.

Evidence of an interaction between arm and the baseline mean number ofcigarettes (model covariate) was assessed by the parallelism between thearms of the straight-line relationships between the Cigarette Score andthe baseline mean number of cigarettes. The P value for this assessmentof parallelism as shown in the scatter graph (FIG. 17) was 0.2754,providing no evidence of the absence of parallelism.

Alternative Cigarette Score Analyses

The primary outcome was based on the number of cigarettes smoked on eachday from a diary. The Cigarette Score used the diary data for theplanned 25 days while on study treatment. Presented are sensitivityanalyses for the comparison of the 3.0 mg TID arm and the pooled placeboarm related to variations on the primary analysis of Cigarette Score.The alternative definition of the Cigarette Score featured cigarettesrecorded in the diary after the planned quit period of Days 5-7, thatis, from Day 8 onward, instead of from Day 1 onward.

Another alterative analysis was based on re-analyses of the primaryCigarette Score and the above alternative Cigarette Score, with a weightrelated to the standard error of the mean number of cigarettes estimatedfrom the diary entries. The weight used for each subject was 1/(SE)²,where SE is the standard error of the mean estimate, and this type ofweighting, referred to as inverse variance weighting, is used commonly.This weighting gives greater weight to means that are estimated with asmaller SE. A small modification to this definition of weight wasnecessary, however. In computing 1/(SE)², a specific rule was used whenSE=0, specifically when all diary entry values were equal. In thesecases, the SE was computed as if one and only one of the recorded valueswas larger by one. It can be shown that when this modification to thedata is made SE=1/N, where N is the number of the subjects daily (days)entries.

Table 7 shows the P values and effect estimates with 95% confidenceinterval for the four analyses described for the comparison of the 3.0mg TID arm to the pooled placebo arm. When the diary data start was Day8 instead of Day 1, the effect estimate is somewhat more favorable(−11.8 versus −9.5, respectively, for the primary Cigarette Score)because smoking data prior to the planned quit day were excluded. Forthe analyses where weighting was applied to the primary Cigarette Score,the effect estimate P value was 0.0466 compared to 0.0675 for theunweighted analysis of the primary Cigarette Score. This was becausediary data prior to the planned quit day (prior to Day 8) followed byquitting resulted in larger SEs, thereby decreasing the weight forquitters. This decrease in weighting does not apply to the re-definedCigarette Score using diary data starting at Day 8, and therefore theweighted effect size of the re-defined Cigarette Score was distinctlymore favorable than compared to the unweighted primary Cigarette Scorestarting on Day 1 (−15.0 versus −9.5, respectively).

TABLE 7 P Values and Effective Estimates P value (3.0 Weighted mg TIDversus Effect estimate analysis Diary start day of outcome CigaretteScore pooled (95% confidence as defined analyzed placebo) interval) NoStart of intervention (primary outcome) 0.0466  −9.5 (−18.8, −0.2) QuitDay (8th day after start of intervention) 0.0326 −11.8 (−22.5, −1.0) YesStart of Intervention 0.0675 −11.8 (−24.4, 0.9)  Quit Day (8th day afterstart of intervention) 0.0006 −15.0 (−23.3, −6.7)

The analysis of whether there was evidence of effect heterogeneityacross the 8 clinical sites (subject sources) was done as an EMA wherethe interaction P value provided a measure of heterogeneity of effect.This analysis was done for both the Cigarette Score primary outcomevariable and Cess/W5-8/CO Success. For the Cigarette Score, the EMAmodel has additional covariates for BMI stratification and the meannumber of cigarettes reported by screening diary. For Cess/W5-8/COSuccess, no covariates were added to the EMA model due to the likelihoodof empty cells in the cross classification over the discrete variablesof binary outcome, arm, and clinical sites. For example, there weresituations where a specific clinical site had no subjects with successin one or both arms.

FIGS. 18-25 provide EMA analysis results for each of the fourcomparisons of active cytisine arms to the pooled placebo arm, and forboth outcome variables. No evidence of effect heterogeneity due toclinical site was found from any of these EMAs, that is, the interactionP values are not small enough to induce concern regarding clinical siteheterogeneity.

1.5 Comparison of Quit Rates for Cytisinicline and Chantix®

FIG. 12 and Table 8 show the study design for comparing cytisinicline(cytisine) and Chantix®. The treatment duration of Chantix® (12 weeks)was approximately 3.5 times longer than that of cytisinicline (25 days).The sustained abstinence timepoint of Chantix® (12 weeks measured overlast 4 week on treatment) was longer than the that of cytisinicline (8weeks measured over 4 weeks after end of treatment). Table 8 includesadditional details regarding trials with cytisinicline and Chantix®.

TABLE 8 Study Details for Comparing Cytisinicline and Chantix ® ORCA-1Chantix ® Number of subjects 1.5 mg titration 51 EAGLES 3.0 mg titration50  Chantix ® 1005 1.5 mg TID 52  Placebo 1009 3.0 mg TID 50  ONCKENPlacebo 51  Chantix ®  130 Placebo  129 Duration of Treatment 25 Days 12weeks Frequent doctor visits & ✓ ✓ Behavioral support Biochemicalconfirmation Exhaled CO Exhaled CO Quit Rates 4 Weeks ✓ ✓ (ONCKEN) Endof Treatment 4 weeks 12 weeks (EAGLES) 8 Weeks Sustained quit ✓ ✓(EAGLES) (4 weeks after treatment)

FIG. 13 shows the CO confirmed quit rates between 3.0 mg ofcytisinicline and 3.0 mg of Chantix® at 4 weeks and at 12 weeks oftreatment. Chantix® data is 7-day point prevalence, whereascytisinicline is 1-day point prevalence. The CO-confirmed end oftreatment quit rate for subjects treated with 3.0 mg of cytisiniclineexceeded that of subjects treated with 3.0 mg of Chantix® at both Week 4and Week 12 (end of Chantix® treatment). Cytisinicline had a greaterefficacy compared to Chantix®.

FIG. 14 and Tables 9-11 show the odds ratio of cytisinicline andChantix® at 4 weeks, end of treatment, and 4 weeks off treatment.Cytisinicline and Chantix® have similar odd ratios and efficacy. Whilethe 95% CI of both treatments overlap, the odd ratios of thecytisinicline treatment are consistently better than that of Chantix®.

TABLE 9 Odd Ratios of Cytisinicline and Chantix ® at End of TreatmentCytisinicline Placebo Chantix ® Placebo Quit Rate 54.0% 15.7% 38.0%13.7% Drug-placebo difference 38.3% 24.3% OR 6.3 4.0 Lower CI_(95%) 2.473.20 Upper CI_(95%) 16.11 5.0

TABLE 10 Odd Ratios of Cytisinicline and Chantix ® at 4 Weeks TreatmentCytisinicline Placebo Chantix ® Placebo Quit Rate 54.0% 15.7% 37.7%16.3% Drug-placebo difference 38.3% 21.4% OR 6.3 3.1 Lower CI_(95%) 2.471.73 Upper CI_(95%) 16.11 5.99

TABLE 11 Odd Ratios of Cytisinicline and Chantix ® at 4 Weeks OffTreatment Cytisinicline Placebo Chantix ® Placebo Quit Rate 30.0% 7.8%33.2% 12.5% Drug-placebo difference 22.2% 20.7% OR 5.0 3.5 LowerCI_(95%) 1.54 2.78 Upper CI_(95%) 16.50 4.38

Table 12 shows a recent EAGLES study published in 2018 comparing quitrates in the U.S. compared to non-U.S. regions. This study notessignificantly lower quit rates in the U.S. versus non-U.S. regions. Theoverall quit rate of 22% at 24 weeks for subjects treated with Chantix®was only 16% for U.S. patients (N=1065). The quit rates aresignificantly lower than previous trials with Chantix® that were allU.S.-based. The 24-week quit rates in the EAGLES study were lower than52-week quit rates in pivotal trials. The outcomes for abstinenceassociated with younger ages of initial smoking and with U.S. originswere poor.

TABLE 12 Quit Rates in USA versus Non-USA Varenicline Placebo CAR weeks9-24 Versus placebo CAR weeks 9-24 Covariate % (95% CI) OR (95% CI) %(95% CI) Region U.S. 16.1 (14.0-18.4) 2.66 (1.99-3.55) 6.7 (5.3-8.4) Non-U.S. 27.9 (25.2-30.8) 2.80 (2.20-3.55) 12.2 (10.2-14.4)

FIG. 15 shows the odds ratio of cytisinicline at 4 weeks, end oftreatment, and 4 weeks off treatment compared to current products. Whilethe 94% CI of the treatments marginally overlap, the odd ratios of thecytisinicline treatment are consistently better than that of NRT,Zyban®, and Chantix®.

1.6 Analysis of Baseline Attributes and Smoking Status

Effect Modification Analysis of Baseline Patient Attributes

A collection of baseline attributes including age, race, sex, durationof smoking, and number of quit attempts, were analyzed for both theCigarette Score primary outcome variable and Cess/W5-8/CO Success (FIGS.26 and 27). Only the comparison between the cytisine 3.0 mg TID arm andthe pooled placebo arm are presented. The same EMA models used foranalyzing clinical sites were used. The forest graphs for these analysesfollow. (Note: In these forest graphs a (M), (T), or (Q) at the end of afactor label indicates that the pooled data were split by the median,tertiles, or quartiles, respectively. Hx denotes “History”.)

The only interaction P value of note was that for the duration ofsmoking history split by quartiles (“Smoke Hx Dur (y) (Q)”) for theCigarette Score, with P=0.0800. Since the other smoking history durationvariables did not have significant P values (P≥0.2566) this finding wasregarded as unimportant. None of the other factors raised concern aboutheterogeneity of effect.

Effect Modification Analysis of History for Anti-smoking Interventions

Prior anti-smoking intervention factors were analyzed for the CigaretteScore primary outcome variable and Cess/W5-8/CO Success comparing thecytisine 3.0 mg TID arm to the pooled placebo arm (FIGS. 28 and 29). Thefactors analyzed include: whether more than 2 anti-smoking interventionattempts, and if ever treated or recently treated with any of Chantix®,Zyban®, vaping, or nicotine replacement therapy. The same EMA modelsused for analyzing clinical sites were performed. The forest graphs forthese analyses follow.

The only interaction P value of note was that for history of prior useof Chantix® (“Chantix® Hx”) for the Cigarette Score, with P=0.0508.However, the interaction P value for the factor variable indicatingChantix® as the most recent intervention (“Chantix® Most Recent”) didnot indicate concern (P=0.3179). Since the interaction appeared to bequantitative and the finding for most recent use was discordant, theconcern for Chantix® being an effect modifier was discounted.

Effect Modification Analysis of Baseline Laboratory Markers Related toSmoking

Baseline laboratory factors were analyzed for the Cigarette Scoreprimary outcome variable and Cess/W5-8/CO Success comparing the cytisine3.0 mg TID arm to the pooled placebo arm (FIGS. 30 and 31). Thesefactors included nicotine metabolism ratio (NMR), expired CO, and serumcotinine, and were analyzed by median, tertiles, and quartiles. The sameEMA models used for analyzing clinical sites were performed. The forestgraphs for these analyses follow in FIG. 30 and FIG. 31. (Note: In theseforest graphs a (M), (T), or (Q) at the end of a factor label indicatesthat the pooled data were split by the median, tertiles, or quartiles,respectively.)

Only the interaction P values of 0.0434 and 0.0652 for the median andtertile splits of baseline cotinine, respectively, for the CigaretteScore met the criterion suggesting effect modification. However, theinteraction P values for the continued abstinence secondary outcome were0.2925, 0.3738, and 0.9732 for the median, tertile, and quartile splits,respectively, showing no effect modification regarding baseline cotininelevels. Since 4-week abstinence is planned to be the primary outcome forfuture Phase 3 studies, concern for baseline cotinine as an effectmodifier is of less concern.

1.7 Tipping Point Analysis for Smoking Cessation Weeks 5-8

A tipping point analysis was performed for Cess/W5-8/CO Success for thecytisine 3.0 mg TID arm versus the pooled placebo arm comparison and isshown in FIG. 32. The goal of the tipping point analysis was to assessthe degree to which the re-assignment of cases defined as failure due toinadequacy of assessment data would influence results. The tipping pointevaluation re-analyzed the data for all possible reversals of thefailure assignment to a success, with a graph illustrating whichre-assignments met statistical criterion. The horizontal axis representsthe number of possible control arm re-assignments and the vertical axisrepresents the number of possible experimental arm re-assignments. Eachcombination of re-assignment was re-analyzed to assess whether thestatistical criterion was met. The lower left point represents the casewhere there are no re-assignments (that is, the planned analysis). Theregion where re-assignments met statistical criterion is patterned,whereas the region where re-assignments do not meet statisticalcriterion is grey.

There were 6 control arm cases and 3 experimental arm cases that wereeligible for re-assignment. The most important finding from this graphis that if there either are 0 or 1 re-assignments in the experimentalarm, then the statistical criterion will not be met when there are 3 ormore re-assignments in the control arm. Similarly, if there either are 2or 3 re-assignments in the experimental arm, then the statisticalcriterion will not be met when there are 5 or more re-assignments in thecontrol arm. Thus, the continued abstinence secondary outcome was robustagainst re-assignments.

In summary, results for an initial quit rate at Week 4 for allcytisine-treated arms demonstrated significantly increased initial rates(50% to 54%) compared with pooled placebo (16%), and with ORs rangingfrom 5.38 to 6.31. Prolonged abstinence from Weeks 5 to 8 (i.e., for 4weeks off treatment) also demonstrated significantly increased prolongedquit rates of 16% to 30% in the cytisine-treated arms compared to 8% forpooled placebo and with ORs ranging from 3.23 to 5.04. Overall, theinitial and prolonged quit rates were highest for the 3.0 mg TID arm at54% and 30%, respectively, and with the greatest ORs of 6.31 and 5.04,respectively.

Safety Analysis

Overall, there were no safety concerns following dosing in the 1.5 mg ofcytisine or 3.0 mg treatment arms on both schedules, and no new orunexpected AEs were identified during the study.

Table 13 summarizes the treatment emergent adverse events (TEAEs). TEAEswere experienced by approximately half the study population in alltreatment arms. The TID dosing schedule had slightly fewer TEAEsoverall. Across both schedules, the SOCs with the highest incidence ofTEAEs in any treatment arm were infections and infestations, psychiatricdisorders, and gastrointestinal disorders. Common TEAEs were AEs thathad been previously reported in other studies or within theInvestigator's Brochure. All TEAEs were mild or moderate in severity onthe commercial schedule and all events except 2 were mild or moderate onthe TID schedule: One experienced a severe head injury, and anothersubject experienced a severe case of influenza. Neither event wasconsidered related to the study drug.

TABLE 13 Summary of the TEAEs in the Study Population TID DownwardTitration Pooled 1.5 mg 3.0 mg 1.5 mg 3.0 mg Cytisinicline Placebo (n =52) (n = 50) (n = 51) (n = 50) (n = 203) (n = 51) At least 1 AE 20 (39%)21 (42%) 29 (57%) 23 (46%) 93 (46%) 24 (47%) URTI 5 (10%) 3 (6%) 3 (6%)2 (4%) 13 (6%) 7 (14%) Abnormal 4 (8%) 3 (6%) 4 (8%) 7 (14%) 18 (9%) 1(2%) dreams Nausea 1 (2%) 3 (6%) 5 (10%) 3 (6%) 12 (6%) 5 (10%) Insomnia4 (8%) 3 (6%) 3 (6%) 4 (8%) 14 (7%) 1 (2%) Headache 6 (12%) 2 (4%) 1(2%) 1 (2%) 10 (5%) 2 (4%) Fatigue 3 (6%) 1 (2%) 1 (2%) 2 (4%) 7 (3%) 2(4%) Constipation 1 (2%) 3 (6%) — — 4 (2%) 1 (2%) *≥5% (3 subjects) inany treatment arm

There were no relevant mean changes or shifts from baseline inlaboratory parameters over time or 12-lead ECG results. The overallincidence of potentially clinically significant changes in vital signmeasurements was low, with the lowest incidence occurring on the TIDschedule.

Table 14 summarizes the TEAEs of cytisinicline compared to Chantix® in aprevious 2016 study. TEAEs were experienced by less than 30% the studypopulation treated with either cytisinicline, Chantix®, or placebo.Subjects treated with Chantix® experienced the highest incidence ofTEAEs compared to cytisinicline and placebo. Most incidences of TEAEswith cytisinicline treatment was only marginally higher than placebo.

TABLE 14 TEAEs of cytisinicline compared to Chantix ® in 2016 StudyORCA-1 Cochrane Cytisinicline Placebo Chantix ® (n = 203) (n = 51) (n >7000) Serious AEs 0 0 3.3% Abnormal dreams 18 (9%) 1 (2%) 12.5% Headache10 (5%) 2 (4%) 12.7% Insomnia 14 (7%) 1 (2%) 14.2% Nausea 12 (6%)  5(10%) 27.8%

In summary, there were no serious or severe adverse events and there wasa low incidence of overall adverse events. The results from the studyfurther demonstrate that there were no clinically-significant changes invital signs, routine hematology and/or chemistry, and no changes in ECG.Overall, no new safety signals were observed during the conduct of thisstudy.

CONCLUSION

The results from the study indicated that cytisine benefit occurred allbaseline characteristics and attributes. In specific, the cytisinebenefit occurred across subject demographics, baseline CO levels and thenumber of cigarettes smoked daily, as well as based on smoking history.In terms of subject demographics, the benefit was consistent across thesubject population regardless of race, gender, age, and BMI. Inaddition, in terms of smoking history, regardless of the duration ofsmoking, quit attempts, and history of prior smoking cessationmedication use (e.g., Chantix®, Zyban®, NRT, vaping), the subjectsexhibited the same benefit from administration of cytisine.

The results further demonstrated that subjects exhibited a similarbenefit upon administration of cytisine irrespective of their ability tometabolize nicotine. In particular, no treatment relationship wasobserved based on the baseline nicotine metabolite ratio of the subjectsand there was a similar cytisine benefit for fast and slow nicotinemetabolizers.

Results from the primary analyses demonstrated a reduction in percentageof expected cigarettes smoked in both schedules versus pooled placebo.Results for the initial quit rate endpoint demonstrated both cytisinearms of the TID schedule had high odds of success compared with placebo;subjects in the 3.0 mg of cytisine arm had the best odds of success forquitting smoking at Week 4.

For the prolonged abstinence from Week 5 to Week 8 endpoint, both armsof the TID schedule had high odds of success compared with placebo;subjects in the 3.0 mg of cytisine arm had the best odds of success forabstinence from Weeks 5 to 8. The study demonstrated that cytisine is aneffective aid to smoking cessation with an advantageous adverse eventprofile, and 3.0 mg TID dosing is more efficacious overall, with noincrease in adverse events.

Overall, there were no safety concerns following dosing in the 1.5 mg ofcytisine or 3.0 mg arms on either schedule.

Example 2: Impact of Continued Treatment with Cytisine on SmokingCessation

This Example describes a Phase 3, multi-center, double-blind,randomized, placebo-controlled trial designed to evaluate the efficacyand safety of cytisine in adult smokers. This study is designed toimprove efficacy outcomes and to determine whether continued treatmentcan prevent early smoking relapse. The study is designed to evaluatetreatment across 3 treatment arms: placebo (A), treatment with cytisine(e.g., cytisinicline) for 6 weeks (B), and treatment with cytisine for12 weeks (C) as shown in the schematic of FIG. 33. Subjects arerandomized to one of the three arms A, B, or C. In Arm A, subjects aretreated with a placebo for 12 weeks plus behavioral support. In Arm B,subjects are treated with 3.0 mg cytisinicline TID for 6 weeks followedby a placebo for 6 weeks plus behavioral support. In Arm C, subjects aretreated with 3.0 mg cytisinicline TID for 12 weeks plus behavioralsupport. Cytisine treatment will be evaluated in the study populationfor 6 or 12 weeks, with a primary efficacy endpoint of 4-weeks ofcontinuous abstinence while on treatment and will include a 6-monthfollow-up period.

2.1 Study Objectives

2.1.1 Co-Primary Efficacy Objectives

The co-primary efficacy objectives of the study, which will be based ontwo comparisons where study success can be based on success for eithercomparison, will be the following:

-   -   To assess whether subjects randomized to Arm B have a higher        probability of abstinence from Week 3 to Week 6        post-randomization as compared to subjects randomized to Arm A;        and    -   To assess whether subjects randomized to Arm C have a higher        probability of abstinence from Week 9 to Week 12        post-randomization as compared to subjects randomized to Arm A.

2.1.2 Secondary Efficacy Objectives

If the corresponding primary comparison passes statistical criterion,then analysis for the following secondary objectives will be performed.The secondary efficacy objectives of the study will be the following:

-   -   To assess whether subjects randomized to Arm B have a higher        probability of continuous abstinence from Week 6 to Week 24        post-randomization as compared to subjects randomized to Arm A;        and    -   To assess whether subjects randomized to Arm C have a higher        probability of continuous abstinence from Week 12 to Week 24        post-randomization as compared to subjects randomized to Arm A.

If the co-primary comparisons pass statistical criterion, then analysisfor the following additional secondary objective will be performed. Theadditional secondary efficacy objective of the study will be thefollowing:

-   -   To assess for a reduction in risk of relapse from Week 6 to Week        24 in subjects receiving 3.0 mg cytisinicline for 6 weeks and        then either continue 3.0 mg cytisinicline from Week 6 to Week 12        (Arm C) or were switched to placebo from Week 6 to Week 12 (Arm        B).

Subjects not abstinent at Week 6 will be regarded as having relapsed.

2.1.3 Other Objectives

Other objectives of this study will be the following:

-   -   To compare arms (Arm B versus Arm A; Arm C versus Arm A) on        7-day point prevalence abstinence weekly at Week 2 to Week 12,        then for Weeks 16, 20, and 24;    -   To compare arms (Arm B versus Arm A; Arm C versus Arm A) on        serum cotinine levels every other week at Week 2 to Week 12,        then at Weeks 16, 20, and 24;    -   To compare arms (Arm B versus Arm A; Arm C versus Arm A) on        expired CO levels every week at Week 2 through Week 12, then at        Weeks 16, 20, and 24;    -   To compare arms (Arm B versus Arm A; Arm C versus Arm A) on use        of any non-cigarette nicotine products, including vaping, during        study treatment at Week 2 through Week 12 and study follow-up at        Week 16 through Week 24;    -   To assess whether subjects randomized to Arm B have a higher        probability of abstinence from Week 9 to Week 12 as compared to        subjects randomized to Arm A (placebo);    -   To assess among the subset of subjects who achieve abstinence        from Week 3 to Week 6, whether subjects randomized to Arm B have        a higher probability of continuous abstinence from Week 3 to        Week 24 post-randomization as compared to subjects randomized to        Arm A;    -   To assess among the subset of subjects who achieve abstinence        from Week 9 to Week 12, whether subjects randomized to Arm C        have a higher probability of continuous abstinence from Week 9        to Week 24 post-randomization as compared to subjects randomized        to Arm A;    -   Among subjects who achieve abstinence from Week 3 to Week 6, to        compare time to failure to maintain abstinence between arms (Arm        B versus Arm A; Arm C versus Arm A) to Week 24;    -   To explore the magnitude of treatment effect between arms across        various subgroups defined by demographic and baseline        characteristics for the primary and secondary outcomes; and    -   To explore potential relationships between subject-reported        outcomes (e.g., anxiety, depression, withdrawal symptoms, and        tobacco craving) and the primary and secondary outcomes.

2.1.4 Safety Objectives

The safety objectives of the study will be the following:

-   -   To evaluate the safety profile of 3.0 mg TID cytisinicline        compared to placebo (e.g., Arm B versus Arm A and Arm C versus        Arm A);    -   To compare the safety profiles of Arm B subjects versus Arm C        subjects with respect to adverse events occurring after Week 6        on the study.

2.2 Study Design

The population for this study will be male or female adults who aredaily cigarette smokers, intending to quit smoking, and are willing toset a quit date that is within 5 to 7 days of the start of treatment.Study treatment will start the day after randomization.

Subjects will meet all requirements outlined in inclusion and exclusioncriteria. A total of approximately 750 subjects will be randomlyassigned with equal probability to one of three Arms (Arm A, 12 weeksplacebo: N=250; Arm B, 6 weeks cytisinicline followed by 6 weeksplacebo: N=250; Arm C, 12 weeks of cytisinicline: N=250) as shown inFIG. 33.

Each randomized subject will receive 12 weeks of treatment using a TIDdosing schedule. Smoking cessation assessments will begin on Week 2 (Day14±1 post-randomization) and will continue weekly during the TreatmentPeriod through the Week 16, 20, and 24 Follow-up Period visits by thesubject's self-report of abstinence with CO biochemical verification.

All subjects will receive concurrent smoking cessation behavioralsupport during the study Treatment Period (Week 1-12). Additionalbehavioral support will be provided during the Follow-up Period based onissues, concerns, and/or questions raised by the subject.

Safety assessments at clinic visits will occur on Day 2 and Day 7 duringWeek 1 and then weekly throughout the Treatment Period. Laboratoryhematology and chemistry assessments will be made on Day 7, Week 6, andWeek 12 (End of Treatment “EOT”) during the Treatment Period. Anyongoing adverse events at Week 12 will be followed until resolved ordetermined to be chronic. The end of study is defined as the lastfollow-up visit (up to the Week 24 visit) for the last subject.

2.3 Treatment Period

The Treatment Period will begin on the day after randomization. Studytreatment will be blinded, and subjects will take one study tablet threetimes during the day, approximately 5 hours apart. Subjects randomlyassigned to Arm A will take one placebo tablet at each dosing per dayfor 12 weeks. Arm B subjects will take one cytisinicline tablet at eachdosing per day for the first 6 weeks followed by one placebo tablet ateach dosing per day for the last 6 weeks. Arm C subjects will take onecytisinicline tablet at each dosing per day for 12 weeks.

2.4. Inclusion Criteria

Subjects meeting all of the following criteria will be eligible toparticipate in the study:

-   -   Male or female subjects years of age.    -   Current daily cigarette smokers (averaging at least 10        cigarettes per day upon completing a 7-day screening smoking        diary) and who intend to quit smoking.    -   Expired air CO 0 ppm.    -   Failed at least one previous attempt to stop smoking with or        without therapeutic support.    -   Willing to initiate study treatment on the day after        randomization and set a quit date within 5 to 7 days of starting        treatment.    -   Willing to actively participate in the study's smoking cessation        behavioral support provided throughout the study.    -   Able to fully understand study requirements, willing to        participate, and comply with dosing schedule.    -   Sign the Informed Consent Form.

2.5. Exclusion Criteria

Subjects will be excluded from participation in the study if any of thefollowing criteria apply:

-   -   More than 1 study participant in same household.    -   Previous cytisinicline treatment in a prior clinical study or        any other cytisine usage.    -   Known hypersensitivity to cytisinicline or any of the        excipients.    -   Positive urinary drugs of abuse screen determined within 28 days        before the first dose of cytisinicline.    -   Clinically significant abnormal serum chemistry or hematology        values within 28 days of randomization (i.e., requiring        treatment or monitoring).    -   Clinically significant abnormalities in 12-lead ECG determined        after minimum of 5 minutes in supine position within 28 days of        randomization (i.e., requiring treatment or further assessment).    -   BMI classification for being underweight (<18.5 kg/m2) or having        Class 2 obesity (35 kg/m2).    -   Recent history (within 3 months) of acute myocardial infarction,        unstable angina, stroke, cerebrovascular incident, or        hospitalization for congestive heart failure.    -   Current uncontrolled hypertension (blood pressure 160/100 mmHg).    -   Documented diagnosis of schizophrenia or bipolar psychiatric        illness; currently psychotic; having suicidal ideation/risk        (“Yes” to question 4 or question 5 OR “Yes” to any suicidal        behavior question on the C-SSRS); or current symptoms of        moderate to severe depression (HADS score 1).    -   Renal impairment defined as a creatinine clearance (CrCl)<60        mL/min (estimated with the Cockroft-Gault equation).    -   Hepatic impairment defined as alanine aminotransferase (ALT) or        aspartate aminotransferase (AST)>2.0× the upper limit of normal        (ULN).    -   Women who are pregnant or breast-feeding.    -   Male or female subjects of child bearing potential who do not        agree to use acceptable methods of birth control during the        study treatment period.    -   Participation in a clinical study with an investigational drug        in the 4 weeks prior to randomization.    -   Treatment with other smoking cessation medications (bupropion,        varenicline, nortriptyline, or any nicotine replacement therapy        [NRT]) in the 4 weeks prior to randomization or planned use of        these other smoking cessation medications during the study.    -   Use within the 2 weeks prior to randomization or planned use        during the study of non-cigarette and/or noncombustible nicotine        products (pipe tobacco, cigars, snuff, smokeless tobacco,        hookah, e-cigarettes/vaping) or marijuana smoking or vaping.    -   Any other reason that the investigator views the subject should        not participate or would be unable to fulfill the requirements        for the study.

2.6 Previous and Concomitant Medications

All subjects will continue to receive any existing prescriptionmedication. Every effort will be made to ensure that the regimen ofexisting medications remain stable during the study.

At the discretion of the Investigator, the use of non-study drugmedications (either prescription or over-the-counter) may be given ifclinically-indicated during the study. Full details of any newmedications will be recorded in the subject's Case Report Form (CRF).

All concomitant medication(s) taken during the trial, and any changes(additions, deletions, dose changes) will be recorded in the CRF.

2.7 Treatment Compliance

Treatment compliance will be monitored during the 84-day (12-week)Treatment Period via review of dose timing and drug accountability.Subjects will have a daily treatment diary that will record the numberof tablets taken and time taken. Subjects will be instructed to bringtheir medication packs (blister packs) to each clinic visit so thatclinic staff can reconcile against the treatment diary, recording thenumber of tablets taken and the number of missed tablets. In addition,an optional text messaging system will be implemented that will provideeach subject with reminder texts corresponding to the approximate timeof dosing.

2.8 Study Procedures

After providing signed informed consent, all subjects will be evaluatedfor inclusion in the study within a 28-day Screening Period. Subjectswho meet inclusion criteria will be required to provide a quit date thatmust be within 5-7 days after the start of treatment and agree toinitiating study treatment the day after randomization. Both plannedquit and treatment start dates will be documented to confirm inclusion.Once all eligibility criteria are confirmed, randomization can occur.Study Day 1 will be defined as the first day of treatment. Subjects willcomplete a clinic visit on Day 2, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70,77, and 86. Follow-up visits will be scheduled at Week 16, 20, and 24.

2.8.1 Procedure Schedule

Table 15 provides a summary of required study evaluations. Screeningevaluations will occur within a 28-day interval from initiation ofscreening evaluations to randomization. Subjects will initiate studytreatment the day after randomization, such that study treatment isinitiated on Day 1 prior to the quit date, within 5-7 days of Day 1.

TABLE 15 Schedule of Study Procedures During Treatment Period TreatmentPeriod Week 1-Week 12 (Day 84) Screening Period Random- (Days 7-86 are±1 Day) (Day 28 to Rand) ization W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 EOT³Study Assessment SV 1 SV 2¹ Day 0 D1² D2 (D7) (D14) (D21) (D28) (D35)(D42) (D49) (D56) (D63) (D70) (D77) (D86) Informed Consent •Inclusion/Exclusion • Demographics • Medical and • Psychiatric HistoryC-SSRS • • • Questionnaire⁴ Physical Exam •⁵ Smoking History • UrinePregnancy • • • • • Test for all Females⁶ Drugs of Abuse • Screen⁷ VitalSigns •⁸ • • • • • • • • • • • • • • including weight Hematology and • •• • Chemistry 12-lead ECG • • • Concomitant • • • • • • • • • • • • • •• • • Medications Quit Date Set and • Treatment Day 1 Scheduled ReviewSmoking & • • • Treatment Diary Completion Instructions⁹ Review Smoking• • Diary¹⁰ Review Treatment • • • • • • • • • • • • • Diary Entries forCompleteness and Compliance¹¹ Adverse Event • • • • • • • • • • • • • •• • • Reporting Study Drug • • • • • • • • • • • • • • Distribution,Accountability, and Collection Behavioral Support •¹² • • • • • • • • •• • • • • Fagerström Test of • Nicotine Dependence Self-Efficacy •Questionnaire QSU-Brief • • • • • • • • • Questionnaire MNWS • • • • • •• • Questionnaire¹³ HADS • • • Questionnaire Smoking Cessation • • • • •• • • • • • Status Expired CO • • • • • • • • • • • • • Use of any non-• • • • • • • • • • • cigarette nicotine products¹⁴ Serum Cotinine •¹⁵ •• • • • • ¹Randomization may occur at the SV2 visit IF subject cancommit to a quit date that allows start of treatment the following day.In such cases, all Day 0 (Randomization) procedures will be completed atthe SV2 clinic visit. ²Clinic will telephone each subject towards theend of Day 1 (first day of treatment) to make sure subject has takenmedication according to dosing schedule, answer any questions, assessfor adverse events and any concomitant medications, and confirm the Day2 clinic appointment. ³Procedures required at Day 86 or if subjectdiscontinues treatment prior to Week 12. The final day of treatment willbe on Day 84. In order to ensure subject completes all treatment priorto assessments, the End of Treatment visit will be scheduled on Day 86 ±1 Day. ⁴The Screening assessment for suicidal ideation (questions 1-5)will be asked in the temporal context of “within the past 3 months” andthe Suicidal Behavior questions will be asked within the temporalcontext of “within lifetime” in order to fully evaluate current ideationor risk of suicide. Assessments conducted at Week 6 and EOT will ask allquestions in the temporal context of “since last assessment” forsuicidal ideation/risk. ⁵Physical exam may be conducted at either theSV1 or the SV2. ⁶Urine pregnancy test kits supplied to site by centrallaboratory. All other testing performed by a central laboratory. Testresults must be negative at the SV1 and D0 visit for inclusion into thestudy. ⁷Drugs of abuse to include at a minimum amphetamines,methamphetamines, barbiturates, benzodiazepines, cocaine, ecstasy,opiates, and phencyclidine. ⁸To include height at screening for BMIcalculation. ⁹There will be two distinct diaries to be used: Thescreening smoking diary will capture daily cigarette consumption for 7consecutive days so that an average can be obtained to assess InclusionCriteria #2. This on-study treatment diary will assess treatmentcompliance and will capture each study drug dose date and time. ¹⁰Numberof cigarettes smoked daily will be recorded in a 7-day smoking diary tobe completed by the subject between SV1 and SV2. Adequate completion ofthe 7-day screening diary with an average of at least 10 cigarettessmoked per day will be required for inclusion into the study. ¹¹Studysubjects will make daily diary entries noting date and time of eachdose. Sites will review these prior (via on-line access) and duringclinic visits to ensure subject is completing entries in real-time andaccurately. ¹²Setting the quit date and plan will be considered thefirst behavioral support counseling session. ¹³The MNWS questionnaire toassess withdrawal will be administered to all subjects on Day 0 and Week1 (Day 7). Subsequent measurements will only be administered forsubjects that report no cigarettes smoked since the last clinic visit.¹⁴Although planned use during the study is an exclusion criteria, recordany actual use of non-cigarette nicotine products, including vaping.¹⁵Serum will be collected with other laboratory testing at SV#1 forcotinine testing and another sample will be frozen/stored for possibleNicotine Metabolite Ratio (NMR) testing at baseline only. Serumcollected on subjects that are screen-failed will be destroyed.

TABLE 16 Schedule of Procedure During Follow-up Period Follow-up PeriodWeek 16-Week 24¹ (Week Visits ± 3 Days) Study Assessment Week 16 Week 20Week 24 Behavioral Support² • • • Adverse Event Reporting • • • SmokingCessation Status • • • Expired CO • • • Use of any non-cigarettenicotine products³ • • • Serum Cotinine • • • ¹All subjects regardlessof smoking status at Day 84/Week 12 will continue for follow-up at theWeek 16, Week 20, and Week 24 clinic visits. ²Behavioral supportsessions during the Follow-up Period will be abbreviated and based onlyon issues, concerns, and/or questions raised by subject for Week 16, 20,and 24. ³Record any actual use of non-cigarette nicotine products,including vaping.

2.8.2 Subject Diaries

A 7-day smoking diary will be collected during the screening period inorder to capture the number of cigarettes smoked daily for 7 consecutivedays. This data will be used to calculate the average number ofcigarettes smoked per day in order to support Inclusion Criteria #2.

In addition, a study treatment diary will be maintained by each subjectto record date and timing of study drug administrations during theTreatment Period. The diary will be configured into specific sections tosupport the above reporting by the subject.

2.9 Efficacy Criteria

This study will follow general criteria that are applicable to previousand current trials of cessation aids where participants have a definedtarget quit date and there is face-to-face contact with researchers orclinic staff. Endpoint analyses for abstinence (4 weeks abstinencedocumented during the last 4 weeks of treatment) and continuousabstinence (continually documented to Week 24 post-randomization) willinclude the following criteria:

-   -   Self-report of smoking abstinence since the last clinic visit at        each clinic assessment.    -   Biochemical verification of abstinence by expired CO at each        clinic visit.    -   Use of an ‘intention-to-treat’ approach in which data from all        randomized smokers will be included in the analysis.    -   Subjects with an unknown smoking status at the Week 6, Week 12,        and Week 24 assessments or lost to follow-up will be classified        as failed to quit.    -   Self-report of smoking abstinence during the follow-up period        only (Week 12 to Week 24) will follow the Russell Standard.    -   Continually blinded to treatment allocation during collection of        follow-up data to Week 24.

2.9.1 Safety Assessments

All subjects will be monitored for adverse events starting at screening(pre-existing), by telephone contact on Day 1, at clinic visits on Day 2and Day 7 during Week 1, then weekly throughout the Treatment Period(Weeks 2 through 12/EOT) and monthly during the Follow-up Period (seeTable 15 and Table 16). Laboratory (hematology and chemistry)evaluations will be performed at the Week 1, Week 6, and Week 12 clinicvisits using a central laboratory.

Safety will be assessed by consideration of all adverse events reportedby or elicited from the subject and abnormalities detected on hematologyand serum chemistry tests. Worsening of other pre-existing medicalconditions and any changes to concomitant medications/treatments willalso be taken into account in this evaluation.

2.9.2 Laboratory

Routine Laboratory Assessments

Routine laboratory safety samples will be analyzed at screening and atclinic visits as identified in Table 15 for each subject by a centrallaboratory. A decision regarding whether a result outside the referencerange is of clinical significance or not will be made by anInvestigator, and the report will be annotated accordingly. Clinicallysignificant abnormalities occurring during the study will be recorded onthe AE page. The reference ranges for laboratory parameters will also beentered in the database and filed in the Investigator site file.

Hematology: Hemoglobin, red blood cells, white blood cells, neutrophils,lymphocytes, monocytes, eosinophils, basophils, and platelets.

Chemistry: Total protein, albumin, total bilirubin, SGPT (ALT), SGOT(AST), alkaline phosphatase, glucose, sodium, potassium, calcium,creatinine, and urea.

Expired Air CO

Expired CO will be obtained using a calibrated instrument (e.g., theBedfont Micro+Smokerlyzer®) provided and maintained by the clinicalsite. Each clinical site will have documentation of instrument used andcurrent calibration. CO values will be reported in parts per million(ppm) at Week 2, weekly through Week 12, and at Week 16, 20, and 24.

Serum Cotinine Levels

Serum samples will be collected for determining cotinine levels at Weeks2, 4, 6, 8, 10, 12, 16, 20, and 24. Baseline cotinine testing will usefrozen serum collected at the SV1 visit for subjects that arerandomized. Cotinine levels will be determined at a central laboratory.

2.9.3 Vital Signs

Systolic/diastolic blood pressure, pulse rate, and oral temperaturemeasurements will be recorded in a seated position. Body weight willalso be recorded. Height will be recorded at Screening Visit #1 for BMIcalculation.

2.9.4 Physical Examination

A physical examination will be performed by an Investigator. Theexamination will include general appearance, head, ears, eyes, nose,throat, neck, skin, cardiovascular system, respiratory system,gastrointestinal system, central nervous system, lymph nodes, andmusculoskeletal. An Investigator can examine other body systems ifrequired, at their discretion.

2.10 Primary Outcome for Subjects

The primary efficacy outcome (biochemically verified abstinence for thelast 4 weeks of cytisinicline treatment) for each subject will bebinary: success versus failure. Success will be defined for the subjectas having reported smoking abstinence (no cigarettes since the lastclinic visit) at each clinic assessment from Week 3 to Week 6 (Arm B)and Week 9 to Week 12 (Arm C) with biochemical verification at eachassessment. Biochemical verification will be defined by a carbonmonoxide concentration in exhaled breath of less than 10 ppm. Similartimeframe and analyses will occur for Arm A placebo subjects.

2.11 Secondary Outcome for Subjects

The secondary efficacy outcome 1 and 2 (continued biochemically verifiedabstinence to Week 24) for each subject will be binary: success versusfailure. Success will be defined for the subject as having reportedsmoking abstinence since the last clinic visit at each clinic assessmentfrom Week 6 (Arm B) or Week 12 (Arm C) to Week 24 with biochemicalverification at each assessment. Biochemical verification will bedefined by a carbon monoxide concentration in exhaled breath of lessthan 10 ppm. During the Follow-up Smoking Cessation Assessment Periodbetween Weeks 12 to 24, self-report of smoking abstinence will beaccording to the Russell Standard.

The secondary efficacy outcome 3 will be success with respect to beingwithout relapse at Week 24. The secondary efficacy outcome 3 (reductionin risk of relapse from Week 6 to Week 24 in Arm C versus Arm B) will beassessed in each subject (in both Arms C and B). Subjects not abstinentat Week 6 will be regarded as having relapsed.

2.12 Safety Objectives

Safety assessments will include reported adverse events, laboratory testresults, and vital signs. Safety variables will be summarized for theSafety Analysis Set (SAS), defined as all randomized subjects who takeat least one dose of study drug.

Adverse events will be coded using the MedDRA dictionary. Coding willinclude system organ class (SOC) and preferred term (PT). All verbatimdescriptions and coded terms will be listed for all AEs. Variousembodiments of the invention are set forth herein below in paragraphs272 to 391:

A method of treating a nicotine addiction, a nicotine dependence,promoting cessation of smoking and/or vaping, and/or promoting areduction in smoking and/or vaping in a subject in need thereof, themethod comprising administering cytisine provided in a unit dose of 3.0mg, 1.5 mg, or 1.0 mg of cytisine three times daily to the subject.

The method of paragraph 272, wherein the subject experiences no adverseevents after receiving the cytisine treatment.

The method of paragraphs 272 and 273, wherein the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation.

The method of paragraphs 272-274, wherein the subject experiences nonausea after receiving the cytisine treatment.

The method of paragraphs 272-275, wherein cytisine is administered forabout 6 weeks or for about 12 weeks.

The method of paragraphs 272-276, wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine.

The method of paragraphs 272-277, wherein the subject is a refractorypatient who has failed treatment with one or more nicotine addiction orsmoking cessation treatments.

The method of paragraphs 272-278, wherein the nicotine addiction orsmoking cessation treatments are selected from NRT, administration ofbupropion, administration of varenicline, electronic cigarettes, vaping,and a combination thereof.

The method of paragraphs 272-279, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The method of paragraphs 272-280, further comprising providingbehavioral support to the subject.

A method of treating of nicotine addiction and/or a nicotine dependencein a subject in need thereof, the method comprising administeringcytisine to the subject, wherein the subject is a refractory patient whohas failed treatment with one or more nicotine addiction treatments.

The method of paragraph 282, wherein the nicotine addiction treatmentscomprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

The method of paragraphs 282 and 283, wherein cytisine is provided in aunit dose of about 1.0 mg to about 6.0 mg of cytisine three to six timesdaily to a subject in need thereof.

The method of paragraphs 282-284, wherein cytisine is provided in a unitdose of 3.0 mg of cytisine three times daily to a subject in needthereof.

The method of paragraphs 282-285, wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine.

The method of paragraphs 282-286, wherein cytisine is administered forabout 6 weeks or for about 12 weeks.

The method of paragraphs 282-287, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The method of paragraphs 282-288, wherein the adverse event is selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation.

The method of paragraphs 282-289, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

A method of preventing smoking and/or vaping relapse in a subject inneed thereof, the method comprising administering cytisine provided in aunit dose of (a) two tablets, each tablet either containing 1.5 mg or3.0 mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0mg of cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine, three times daily to the subject.

The method of paragraph 291, wherein cytisine is administered for about6 weeks or for about 12 weeks.

The method of paragraphs 291 and 292, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The method of paragraphs 291-293, wherein the adverse event is selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation.

The method of paragraphs 291-294, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The method of paragraphs 291-295, wherein the subject is a refractorypatient who has failed treatment with one or more smoking cessationtreatments.

The method of paragraphs 291-296, wherein the smoking cessationtreatments comprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

A method of preventing smoking and/or vaping relapse in a subject inneed thereof, the method comprising administering cytisine to thesubject, wherein the subject is a refractory patient who has failedtreatment with one or more smoking cessation treatments selected fromthe group consisting of NRT, administration of bupropion, administrationof varenicline, electronic cigarettes, and vaping.

The method of paragraph 298, wherein the subject (a) smoked ten or morecigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The method of paragraphs 298 and 299, wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine, and wherein cytisine is administered for about 6 weeks or forabout 12 weeks.

The method of paragraphs 298-300, wherein the subject experiences noadverse events selected from the group consisting of an URTI, abnormaldreams, nausea, insomnia, headache, fatigue, and constipation afterreceiving the cytisine treatment.

A medicament comprising a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg ofcytisine for treating a nicotine addiction, a nicotine dependence,promoting cessation of smoking and/or vaping, and/or promoting areduction in smoking and/or vaping in a subject in need thereof, whereinthe medicament is for three times daily oral administration to thesubject.

The medicament of paragraph 302, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The medicament of paragraphs 302 and 303, wherein the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation.

The medicament of paragraphs 302-304, wherein the subject experiences nonausea after receiving the cytisine treatment.

The medicament of paragraphs 302-305, wherein cytisine is administeredfor about 6 weeks or for about 12 weeks.

The medicament of paragraphs 302-306, wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine.

The medicament of paragraphs 302-307, wherein the subject is arefractory patient who has failed treatment with one or more nicotineaddiction or smoking cessation treatments.

The medicament of paragraphs 302-308, wherein the nicotine addiction orsmoking cessation treatments are selected from NRT, administration ofbupropion, administration of varenicline, electronic cigarettes, vaping,and a combination thereof.

The medicament of paragraphs 302-309, wherein the subject (a) smoked tenor more cigarettes per day prior to the administration of cytisine, (b)has expired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The medicament of paragraphs 302-310, further comprising providingbehavioral support to the subject.

A medicament comprising cytisine for treating a nicotine addiction or anicotine dependence in a subject that is a refractory patient who hasfailed treatment with one or more nicotine addiction treatments, whereinthe medicament is for three times daily oral administration to thesubject.

The medicament of paragraph 312, wherein the nicotine addiction ordependence treatments comprise NRT, administration of bupropion,administration of varenicline, electronic cigarettes, vaping, or acombination thereof.

The medicament of paragraphs 312 and 313, wherein cytisine is providedin a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to sixtimes daily to a subject in need thereof.

The medicament of paragraphs 312-314, wherein cytisine is provided in aunit dose of 3.0 mg of cytisine three times daily to a subject in needthereof.

The medicament of paragraphs 312-315, wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine.

The medicament of paragraphs 312-316, wherein cytisine is administeredfor about 6 weeks or for about 12 weeks.

The medicament of paragraphs 312-317, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The medicament of paragraphs 312-318, wherein the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation.

The medicament of paragraphs 312-319, wherein the subject (a) smoked tenor more cigarettes per day prior to the administration of cytisine, (b)has expired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

A medicament comprising a unit dose of cytisine in (a) two tablets, eachtablet either containing 1.5 mg or 3.0 mg of cytisine, (b) a singletablet either containing 1.5 mg or 3.0 mg of cytisine, or (c) threetablets, each tablet containing 1.0 mg of cytisine for preventingsmoking and/or vaping relapse in a subject in need thereof, wherein themedicament is for three times daily oral administration to the subject.

The medicament of paragraph 321, wherein cytisine is administered forabout 6 weeks or for about 12 weeks.

The medicament of paragraphs 321 and 322, wherein the subjectexperiences no adverse events after receiving the cytisine treatment.

The medicament of paragraphs 321-323, wherein the adverse event isselected from the group consisting of an URTI, abnormal dreams, nausea,insomnia, headache, fatigue, and constipation.

The medicament of paragraphs 321-324, wherein the subject (a) smoked tenor more cigarettes per day prior to the administration of cytisine, (b)has expired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The medicament of paragraphs 321-325, wherein the subject is arefractory patient who has failed treatment with one or more smokingcessation treatments.

The medicament of paragraphs 321-326, wherein the smoking cessationtreatments comprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

A medicament comprising cytisine for preventing smoking and/or vapingrelapse in a subject that is a refractory patient who has failedtreatment with one or more nicotine addiction treatments selected fromthe group consisting of NRT, administration of bupropion, administrationof varenicline, electronic cigarettes, and vaping, wherein themedicament is for three times daily oral administration to the subject.

The medicament of paragraph 328, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The medicament of paragraphs 328 and 329, wherein the unit dose ofcytisine comprises (a) two tablets, each tablet either containing 1.5 mgor 3.0 mg of cytisine, (b) a single tablet either containing 1.5 mg or3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mgof cytisine, and wherein cytisine is administered for about 6 weeks orfor about 12 weeks.

The medicament of paragraphs 328-330, wherein the subject experiences noadverse events selected from the group consisting of an URTI, abnormaldreams, nausea, insomnia, headache, fatigue, and constipation afterreceiving the cytisine treatment.

Use of a unit dose of 3.0 mg, 1.5 mg, or 1.0 mg of cytisine for treatinga nicotine addiction, a nicotine dependence, promoting cessation ofsmoking and/or vaping, and/or promoting a reduction in smoking and/orvaping in a subject in need thereof, wherein the cytisine is for threetimes daily oral administration to the subject.

The use of paragraph 332, wherein the subject experiences no adverseevents after receiving the cytisine treatment.

The use of paragraphs 332 and 333, wherein the adverse event is selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation.

The use of paragraphs 332-334, wherein the subject experiences no nauseaafter receiving the cytisine treatment.

The use of paragraphs 332-335, wherein cytisine is administered forabout 6 weeks or for about 12 weeks.

The use of paragraphs 332-336, wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine.

The use of paragraphs 332-337, wherein the subject is a refractorypatient who has failed treatment with one or more nicotine addiction orsmoking cessation treatments.

The use paragraphs 332-338, wherein the nicotine addiction or smokingcessation treatments are selected from NRT, administration of bupropion,administration of varenicline, electronic cigarettes, vaping, and acombination thereof.

The use of paragraphs 332-339, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The use of paragraphs 332-340, further comprising providing behavioralsupport to the subject.

Use of cytisine for treating a nicotine addiction or a nicotinedependence in a subject that is a refractory patient who has failedtreatment with one or more nicotine addiction treatments, wherein thecytisine is for three times daily oral administration to the subject.

The use of paragraph 342, wherein the nicotine addiction treatmentscomprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

The use of paragraphs 342 and 343, wherein cytisine is provided in aunit dose of about 1.0 mg to about 6.0 mg of cytisine three to six timesdaily to a subject in need thereof.

The use of paragraphs 342-344, wherein cytisine is provided in a unitdose of 3.0 mg of cytisine three times daily to a subject in needthereof.

The use of paragraphs 342-345, wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine.

The use of paragraphs 342-346, wherein cytisine is administered forabout 6 weeks or for about 12 weeks.

The use of paragraphs 342-347, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The use of paragraphs 342-348, wherein the adverse event is selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation.

The use of paragraphs 342-349, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

Use of a unit dose of cytisine in the form of (a) two tablets, eachtablet either containing 1.5 mg or 3.0 mg of cytisine, (b) a singletablet either containing 1.5 mg or 3.0 mg of cytisine, or (c) threetablets, each tablet containing 1.0 mg of cytisine for preventingsmoking and/or vaping relapse in a subject in need thereof, wherein thecytisine is for three times daily oral administration to the subject.

The use of paragraph 351, wherein cytisine is administered for about 6weeks or for about 12 weeks.

The use of paragraphs 351 and 352, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The use of paragraphs 351-353, wherein the adverse event is selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation.

The use of paragraphs 351-354, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The use of paragraphs 351-355, wherein the subject is a refractorypatient who has failed treatment with one or more smoking cessationtreatments.

The use of paragraphs 351-356, wherein the smoking cessation treatmentscomprise NRT, administration of bupropin, administration of varenicline,electronic cigarettes, vaping, or a combination thereof.

Use of cytisine for preventing smoking and/or vaping relapse in asubject that is a refractory patient who has failed treatment with oneor more nicotine addiction treatments selected from the group consistingof NRT, administration of bupropion, administration of varenicline,electronic cigarettes, and vaping, wherein the cytisine is for threetimes daily oral administration to the subject.

The use of paragraph 358, wherein the subject (a) smoked ten or morecigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The use of paragraphs 358 and 359 wherein the unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine, and wherein cytisine is administered for about 6 weeks or forabout 12 weeks.

The use of paragraphs 358-360, wherein the subject experiences noadverse events selected from the group consisting of an URTI, abnormaldreams, nausea, insomnia, headache, fatigue, and constipation afterreceiving the cytisine treatment.

Use of tablets comprising about 1.0 mg or about 1.5 mg of cytisine forthree times daily oral administration of about 3.0 mg of cytisine to asubject to treat a nicotine addiction, a nicotine dependence, promotingcessation of smoking and/or vaping, and/or promoting a reduction insmoking and/or vaping in the subject.

The use of paragraph 362, wherein the subject experiences no adverseevents after receiving the cytisine treatment.

The use of paragraphs 362 and 363, wherein the adverse event is selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation.

The use of paragraphs 362-364, wherein the subject experiences no nauseaafter receiving the cytisine treatment.

The use of paragraphs 362-365, wherein cytisine is administered forabout 6 weeks or for about 12 weeks.

The use of paragraphs 362-366, wherein a unit dose of cytisine comprises(a) two tablets, each tablet either containing 1.5 mg or 3.0 mg ofcytisine, (b) a single tablet either containing 1.5 mg or 3.0 mg ofcytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine.

The use of paragraphs 362-367, wherein the subject is a refractorypatient who has failed treatment with one or more nicotine addiction orsmoking cessation treatments.

The use of paragraphs 362-368, wherein the nicotine addiction or smokingcessation treatments are selected from NRT, administration of bupropion,administration of varenicline, electronic cigarettes, vaping, and acombination thereof.

The use of paragraphs 362-369, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The use of paragraphs 362-370, further comprising providing behavioralsupport to the subject.

Use of tablets comprising about 1.0 mg or about 1.5 mg of cytisine forthree times daily oral administration of about 3.0 mg of cytisine to asubject that is a refractory patient who has failed treatment with oneor more nicotine addiction treatments to treat a nicotine addictionand/or a nicotine dependence in the subject.

The use of paragraph 372, wherein the nicotine addiction treatmentscomprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

The use of paragraphs 372 and 373, wherein cytisine is provided in aunit dose of about 1.0 mg to about 6.0 mg of cytisine three to six timesdaily to a subject in need thereof.

The use of paragraphs 372-374, wherein cytisine is provided in a unitdose of 3.0 mg of cytisine three times daily to a subject in needthereof.

The use of paragraphs 372-375, wherein the unit dose of cytisinecomprises either (a) two tablets, each tablet containing 1.5 mg ofcytisine, or (b) a single tablet containing 3.0 mg of cytisine.

The use of paragraphs 372-376, wherein cytisine is administered forabout 6 weeks or for about 12 weeks.

The use of paragraphs 372-377, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The use of paragraphs 372-378, wherein the adverse event is selectedfrom the group consisting of an URTI, abnormal dreams, nausea, insomnia,headache, fatigue, and constipation.

The use of paragraphs 372-379, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

Use of tablets comprising about 1.0 mg or about 1.5 mg of cytisine forthree times daily oral administration of about 3.0 mg of cytisine to asubject to prevent smoking and/or vaping relapse in the subject.

The use of paragraph 381, wherein cytisine is administered for about 6weeks or for about 12 weeks.

The use of paragraphs 381 and 382, wherein the subject experiences noadverse events after receiving the cytisine treatment.

The use of paragraphs 381-383, wherein the adverse event is selectedfrom the group consisting of an upper respiratory tract infection(URTI), abnormal dreams, nausea, insomnia, headache, fatigue, andconstipation.

The use of paragraphs 381-384, wherein the subject (a) smoked ten ormore cigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The use of paragraphs 381-385, wherein the subject is a refractorypatient who has failed treatment with one or more smoking cessationtreatments.

The use of paragraphs 381-386, wherein the smoking cessation treatmentscomprise NRT, administration of bupropion, administration ofvarenicline, electronic cigarettes, vaping, or a combination thereof.

Use of tablets comprising about 1.0 mg or about 1.5 mg of cytisine forthree times daily oral administration of about 3.0 mg of cytisine to asubject who has failed treatment with one or more nicotine addictiontreatments selected from the group consisting of NRT, administration ofbupropion, administration of varenicline, electronic cigarettes, andvaping to prevent smoking relapse in the subject.

The use of paragraph 388, wherein the subject (a) smoked ten or morecigarettes per day prior to the administration of cytisine, (b) hasexpired air CO concentration of about 10 ppm or greater prior to theadministration of cytisine, or (c) a combination of (a) and (b).

The use of paragraphs 388 and 389, wherein a unit dose of cytisinecomprises (a) two tablets, each tablet either containing 1.5 mg or 3.0mg of cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mgof cytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine, and wherein cytisine is administered for about 6 weeks or forabout 12 weeks.

The use of paragraphs 388-390, wherein the subject experiences noadverse events selected from the group consisting of an URTI, abnormaldreams, nausea, insomnia, headache, fatigue, and constipation afterreceiving the cytisine treatment.

1-10. (canceled)
 11. A method of treating of nicotine addiction in asubject in need thereof, the method comprising administering cytisine tothe subject, wherein the subject is a refractory patient who has failedtreatment with one or more nicotine addiction treatments.
 12. The methodof claim 11, wherein the nicotine addiction treatments comprise NRT,administration of bupropion, administration of varenicline, electroniccigarettes, vaping, or a combination thereof. 13-19. (canceled)
 20. Amethod of preventing smoking and/or vaping relapse in a subject in needthereof, the method comprising administering cytisine provided in a unitdose of (a) two tablets, each tablet either containing 1.5 mg or 3.0 mgof cytisine, (b) a single tablet either containing 1.5 mg or 3.0 mg ofcytisine, or (c) three tablets, each tablet containing 1.0 mg ofcytisine, three times daily to the subject.
 21. The method of claim 20,wherein cytisine is administered for about 6 weeks or for about 12weeks.
 22. The method of claim 20, wherein the subject experiences noadverse events after receiving the cytisine treatment.
 23. The method ofclaim 22, wherein the adverse event is selected from the groupconsisting of an URTI, abnormal dreams, nausea, insomnia, headache,fatigue, and constipation.
 24. The method of claim 20, wherein thesubject (a) smoked ten or more cigarettes per day prior to theadministration of cytisine, (b) has expired air CO concentration ofabout 10 ppm or greater prior to the administration of cytisine, or (c)a combination of (a) and (b).
 25. The method of claim 20, wherein thesubject is a refractory patient who has failed treatment with one ormore smoking cessation treatments.
 26. The method of claim 25, whereinthe smoking cessation treatments comprise NRT, administration ofbupropion, administration of varenicline, electronic cigarettes, vaping,or a combination thereof.
 27. A method of preventing smoking and/orvaping relapse in a subject in need thereof, the method comprisingadministering cytisine to the subject, wherein the subject is arefractory patient who has failed treatment with one or more smokingcessation treatments selected from the group consisting of NRT,administration of bupropion, administration of varenicline, electroniccigarettes, vaping.
 28. The method of claim 27, wherein the subject (a)smoked ten or more cigarettes per day prior to the administration ofcytisine, (b) has expired air CO concentration of about 10 ppm orgreater prior to the administration of cytisine, or (c) a combination of(a) and (b).
 29. The method of claim 27, wherein the unit dose ofcytisine comprises (a) two tablets, each tablet either containing 1.5 mgor 3.0 mg of cytisine, (b) a single tablet either containing 1.5 mg or3.0 mg of cytisine, or (c) three tablets, each tablet containing 1.0 mgof cytisine, and wherein cytisine is administered for about 6 weeks orfor about 12 weeks.
 30. The method of claim 27, wherein the subjectexperiences no adverse events selected from the group consisting of anURTI, abnormal dreams, nausea, insomnia, headache, fatigue, andconstipation after receiving the cytisine treatment.